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Nicosia M, Valujskikh A. Recognizing Complexity of CD8 T Cells in Transplantation. Transplantation 2024; 108:2186-2196. [PMID: 38637929 PMCID: PMC11489323 DOI: 10.1097/tp.0000000000005001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
The major role of CD8 + T cells in clinical and experimental transplantation is well documented and acknowledged. Nevertheless, the precise impact of CD8 + T cells on graft tissue injury is not completely understood, thus impeding the development of specific treatment strategies. The goal of this overview is to consider the biology and functions of CD8 + T cells in the context of experimental and clinical allotransplantation, with special emphasis on how this cell subset is affected by currently available and emerging therapies.
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Affiliation(s)
- Michael Nicosia
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Anna Valujskikh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Shaikh A, Gangaplara A, Kone A, Almengo K, Kabore MD, Ali MA, Xu X, Saxena A, Lopez-Ocasio M, McCoy JP, Fitzhugh CD. Galectin-1 is associated with hematopoietic cell engraftment in murine MHC-mismatched allotransplantation. Front Immunol 2024; 15:1411392. [PMID: 39351218 PMCID: PMC11439684 DOI: 10.3389/fimmu.2024.1411392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Haploidentical hematopoietic cell transplantation (haplo-HCT) is associated with an increased risk of allograft rejection. Here, we employed a major histocompatibility complex (MHC)-mismatched allogeneic HCT (allo-HCT) murine model to better understand the role of Gal-1 in immune tolerance. Transplanted mice were classified into either rejected or engrafted based on donor chimerism levels. We noted significantly higher frequencies of CD4+ T cells, CD8+ T cells, natural killer cells, IFN-γ and TNF-α producing CD4+ T cells, and IFN-γ producing dendritic cells and macrophages in rejected mice. Conversely, we found significantly increased frequencies of regulatory T cells (Tregs), predominantly Helios+, IL-10-producing CD4+ T cells, type 1 regulatory (Tr1) cells, and the proportion of Tr1+Gal-1+ cells in engrafted mice. Further, Gal-1 specific blockade in Tregs reduced suppression of effector T cells in engrafted mice. Lastly, effector T cells from engrafted mice were more prone to undergo apoptosis. Collectively, we have shown that Gal-1 may favor HSC engraftment in an MHC-mismatched murine model. Our results demonstrate that Gal-1-expressing Tregs, especially at earlier time points post-transplant, are associated with inducing immune tolerance and stable mixed chimerism after HCT.
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Affiliation(s)
- Ahmad Shaikh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
- Department of Biology, The Catholic University of America, Washington, DC, United States
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Arunakumar Gangaplara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
- Miltenyi Biotec, Research and Development, Gaithersburg, MD, United States
| | - Abdoul Kone
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Katherine Almengo
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Mariama D. Kabore
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Mohamed A.E. Ali
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Xin Xu
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Ankit Saxena
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Maria Lopez-Ocasio
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - J. Philip McCoy
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Courtney D. Fitzhugh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
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Wang D, Huang B, Zhu C, Wang L, Jin J, Tan J, Li Q, Xiang S, Nan K, Lin S. Efficiency Encapsulation of FK506 with New Dual Self-Assembly Multi-Hydrophobic-Core Nanoparticles for Preventing Keratoplasty Rejection. Adv Healthc Mater 2023; 12:e2203242. [PMID: 37171892 DOI: 10.1002/adhm.202203242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/29/2023] [Indexed: 05/14/2023]
Abstract
Nanoparticles self-assembled by amphiphilic copolymers for loading hydrophobic molecules are intensively investigated. However, their hydrophobic molecule-loading capacity is low due to the limitation of hydrophobic groups in these copolymers. In this regard, new lysine oligomer-based multi-hydrophobic side chain polymers (MHCPs) are synthesized by polymerization of γ-benzyl-l glutamate N-carboxy anhydride initiated by side-chain primary amino groups in lysine oligomer. Each hydrophobic side chain in MHCPs can be self-assembled by hydrophobic interaction to form multi-hydrophobic-core nanoparticles (MHC-NPs) with silkworm cocoon-, grape cluster-, and butterfly-like shapes (depending on hydrophobic-side-chains lengths). To increase their stability, MHC-NPs are dually self-assembled with polyethylene glycol-polyglutamic acid through charge interaction. Each hydrophobic core in MHC-NPs serves as a carrier for hydrophobic molecules, endowing their nanostructure with high loading capacity. MHC-NPs are employed to load tacrolimus (also known as FK506), and the loading amount is 18% and the loading efficiency is 80%, which are higher than those of previously reported nanomicelles self-assembled by linear amphiphilic copolymers. Topical administration of FK506-loaded nanoparticle (FK506-NP) can significantly prolong retention of FK506 on the eye surface. FK506-NP exhibits higher in vivo immunosuppressive effects than free FK506 and commercial FK506 eye drop, as well as a better protective effect against immunotoxicity in the corneal grafts after keratoplasty.
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Affiliation(s)
- Dongmei Wang
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Baoshan Huang
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, China
| | - Chenchen Zhu
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Lei Wang
- Engineering Research Center of Clinical Functional Materials and Diagnosis and Treatment Devices of Zhejiang Province, Wenzhou Institute, UCAS, Wenzhou, Zhejiang, 325000, China
| | - Jiahui Jin
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jingyang Tan
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qing Li
- Engineering Research Center of Clinical Functional Materials and Diagnosis and Treatment Devices of Zhejiang Province, Wenzhou Institute, UCAS, Wenzhou, Zhejiang, 325000, China
| | - Shengjin Xiang
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Kaihui Nan
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, China
| | - Sen Lin
- State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, 325027, China
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, China
- Engineering Research Center of Clinical Functional Materials and Diagnosis and Treatment Devices of Zhejiang Province, Wenzhou Institute, UCAS, Wenzhou, Zhejiang, 325000, China
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Single-Cell RNA sequencing highlights the regulatory role of T cell marker genes Ctla4, Ccl5 and Tcf7 in corneal allograft rejection of mouse model. Int Immunopharmacol 2023; 117:109911. [PMID: 37012887 DOI: 10.1016/j.intimp.2023.109911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 02/02/2023] [Accepted: 02/14/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND A mouse corneal allograft model was induced and single-cell RNA sequencing (scRNA-seq) data of corneal tissues and T cells were analyzed to reveal a T cell-mediated mechanism for corneal allograft rejection in mice. METHODS Corneal tissue samples from a mouse model of corneal allograft were collected for scRNA-seq analysis, followed by quality control, dimensionality reduction, cluster analysis and enrichment analysis. A large number of highly variable genes were identified in mice with corneal allograft. Significant difference existed in immune T cells, especially in CD4 + T cells. RESULTS It was found that T cell marker genes Ctla4, Ccl5, Tcf7, Lgals1, and Itgb1 may play key roles in the corneal allograft rejection. Mice with allograft rejection showed a significant increase in the proportion of CD4 + T cells in the corneal tissues. Besides, Ccl5 and Tcf7 expression was increased in mice with allograft rejection and positively linked to the proportion of CD4 + T cells. Whereas, Ctla4 expression was downregulated and negatively associated with the proportion of CD4 + T cells. CONCLUSION Collectively, Ctla4, Ccl5 and Tcf7 may participate in the rejection of corneal allograft in mice by affecting CD4 + T cell activation.
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Zhu J, Inomata T, Di Zazzo A, Kitazawa K, Okumura Y, Coassin M, Surico PL, Fujio K, Yanagawa A, Miura M, Akasaki Y, Fujimoto K, Nagino K, Midorikawa-Inomata A, Hirosawa K, Kuwahara M, Huang T, Shokirova H, Eguchi A, Murakami A. Role of Immune Cell Diversity and Heterogeneity in Corneal Graft Survival: A Systematic Review and Meta-Analysis. J Clin Med 2021; 10:jcm10204667. [PMID: 34682792 PMCID: PMC8537034 DOI: 10.3390/jcm10204667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022] Open
Abstract
Corneal transplantation is one of the most successful forms of solid organ transplantation; however, immune rejection is still a major cause of corneal graft failure. Both innate and adaptive immunity play a significant role in allograft tolerance. Therefore, immune cells, cytokines, and signal-transduction pathways are critical therapeutic targets. In this analysis, we aimed to review the current literature on various immunotherapeutic approaches for corneal-allograft rejection using the PubMed, EMBASE, Web of Science, Cochrane, and China National Knowledge Infrastructure. Retrievable data for meta-analysis were screened and assessed. The review, which evaluated multiple immunotherapeutic approaches to prevent corneal allograft rejection, showed extensive involvement of innate and adaptive immunity components. Understanding the contribution of this immune diversity to the ocular surface is critical for ensuring corneal allograft survival.
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Affiliation(s)
- Jun Zhu
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Ophthalmology, Subei People’s Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Takenori Inomata
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Strategic Operating Room Management and Improvement, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
- Correspondence: ; Tel.: +81-3-5802-1228
| | - Antonio Di Zazzo
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Koji Kitazawa
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 6020841, Japan;
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Yuichi Okumura
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Strategic Operating Room Management and Improvement, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Marco Coassin
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Pier Luigi Surico
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Kenta Fujio
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Ai Yanagawa
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Maria Miura
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Yasutsugu Akasaki
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Keiichi Fujimoto
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
| | - Ken Nagino
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Akie Midorikawa-Inomata
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Kunihiko Hirosawa
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Mizu Kuwahara
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Tianxiang Huang
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Hurramhon Shokirova
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
| | - Atsuko Eguchi
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Akira Murakami
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
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Khan MA, Shamma T. Complement factor and T-cell interactions during alloimmune inflammation in transplantation. J Leukoc Biol 2018; 105:681-694. [PMID: 30536904 DOI: 10.1002/jlb.5ru0718-288r] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/25/2018] [Accepted: 11/21/2018] [Indexed: 02/06/2023] Open
Abstract
Complement factor and T-cell signaling during an effective alloimmune response plays a key role in transplant-associated injury, which leads to the progression of chronic rejection (CR). During an alloimmune response, activated complement factors (C3a and C5a) bind to their corresponding receptors (C3aR and C5aR) on a number of lymphocytes, including T-regulatory cells (Tregs), and these cell-molecular interactions have been vital to modulate an effective immune response to/from Th1-effector cell and Treg activities, which result in massive inflammation, microvascular impairments, and fibrotic remodeling. Involvement of the complement-mediated cell signaling during transplantation signifies a crucial role of complement components as a key therapeutic switch to regulate ongoing inflammatory state, and further to avoid the progression of CR of the transplanted organ. This review highlights the role of complement-T cell interactions, and how these interactions shunt the effector immune response during alloimmune inflammation in transplantation, which could be a novel therapeutic tool to protect a transplanted organ and avoid progression of CR.
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Affiliation(s)
- Mohammad Afzal Khan
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Talal Shamma
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
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Ablamunits V, Goldstein AJ, Tovbina MH, Gaetz HP, Klebanov S. Acute Rejection of White Adipose Tissue Allograft. Cell Transplant 2017; 16:375-90. [PMID: 17658128 DOI: 10.3727/000000007783464830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
White adipose tissue (WAT) transplantation, although widely used in humans, has been done for cosmetic and reconstructive purposes only. Accumulating evidence indicates, however, that WAT is an important endocrine organ and, therefore, WAT transplantation may become valuable as a replacement therapy for a number of hereditary human diseases. Because the most readily available source for such transplantations would be allogeneic tissue, the mechanisms involved in the rejection of WAT allograft should be explored. We have established a model in which leptin-producing allogeneic WAT is transplanted into leptin-deficient ob/ob mice. Because ob/ob mice are obese, hyperphagic, and hypothermic, WAT allograft function is monitored as the reversal of this leptin-deficient phenotype. Here we report that allografted WAT is primarily nonfunctional. However, when WAT is transplanted into immunodeficient (Rag1–/–) ob/ob mice, or into ob/ob mice depleted of T cells by anti-CD3 antibody, a long-term graft survival is achieved as indicated by the reversal of hyperphagia, weight loss, and normalization of body temperature. The symptoms of leptin deficiency rapidly recur when normal spleen cells of the recipient type are injected, or when the antibody treatment is terminated. In contrast, selective depletion of either CD4+ or CD8+ cells alone does not prevent WAT allograft rejection. Similarly, WAT allografts that do not express MHC class I or class II molecules are rapidly rejected, suggesting that both CD4+ and CD8+ T cells may independently mediate WAT allograft rejection.
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Affiliation(s)
- Vitaly Ablamunits
- Obesity Research Center, St. Luke's Hospital, New York, NY 10025, USA.
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Rowe AM, Yun H, Hendricks RL. Exposure Stress Induces Reversible Corneal Graft Opacity in Recipients With Herpes Simplex Virus-1 Infections. Invest Ophthalmol Vis Sci 2017; 58:35-41. [PMID: 28055100 PMCID: PMC5225994 DOI: 10.1167/iovs.16-19673] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose Most of the inflammation in murine herpes simplex virus type 1 (HSV-1)-induced stromal keratitis (HSK) is due to exposure stress resulting from loss of corneal nerves and blink reflex. Corneal grafts often fail when placed on corneal beds with a history of HSK. We asked if corneal exposure contributes to the severe pathology of corneal grafts on HSV-1–infected corneal beds. Methods Herpes simplex virus type 1–infected corneas were tested for blink reflex. Opacity and vascularization were monitored in allogeneic and syngeneic corneal grafts that were transplanted to corneal beds with no blink reflex or to those that retained blink reflex in at least one quadrant following infection. Results Retention of any level of blink reflex significantly reduced inflammation in HSV-1–infected corneas. Corneal allografts placed on HSV-1–infected beds lacking corneal blink reflex developed opacity faster and more frequently than those placed on infected beds that partially or completely retained blink reflex. Corneal grafts placed on infected corneal beds with no blink reflex rapidly became opaque to a level that would be considered rejection. However, protecting these grafts from exposure by tarsorrhaphy prevented or reversed the opacity in both syngeneic and allogenic grafts. Conclusions Exposure due to HSV-1–engendered hypoesthesia causes rapid, severe, persistent, but reversible opacification of both allogeneic and syngeneic corneal grafts. This opacity should not be interpreted as immunologic rejection. Exposure stress may contribute to the high rate of corneal graft pathology in patients with recurrent HSK.
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Affiliation(s)
- Alexander M Rowe
- University of Pittsburgh Department of Ophthalmology, Pittsburgh, Pennsylvania, United States
| | - Hongmin Yun
- University of Pittsburgh Department of Ophthalmology, Pittsburgh, Pennsylvania, United States
| | - Robert L Hendricks
- University of Pittsburgh Department of Immunology, and Microbiology and Molecular Genetics, Pittsburgh, Pennsylvania, United States
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He Y, Wang B, Jia B, Guan J, Zeng H, Pan Z. Effects of Adoptive Transferring Different Sources of Myeloid-Derived Suppressor Cells in Mice Corneal Transplant Survival. Transplantation 2016; 99:2102-8. [PMID: 26270448 DOI: 10.1097/tp.0000000000000749] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Adoptively transferring different sources of myeloid-derived suppressor cells (MDSCs) may assist in mice corneal transplant survival. METHODS Allogeneic full thickness corneal transplantation (donor C57BL/6 to recipient Balb/c mice) was performed. Naive myeloid cells, inflammation-induced MDSCs (iMDSCs), and tumor-induced MDSCs (tMDSCs) were purified from bone marrow of naive, cecal ligation and puncture, or tumor-bearing Balb/c mice, respectively. The inhibitory abilities of myeloid cells toward CD4(+) T cell proliferation were accessed by in vitro carboxyfluorescein diacetate, succinimidyl ester (CFSE) assays. Myeloid cells were adoptively transferred to corneal recipients by retroorbital injection after corneal transplantation. Corneal grafts were examined and photographed for a period of 45 days. The growth of corneal graft neovascularization was quantitatively measured by image editing software. Histopathology was performed to evaluate corneal graft inflammation. RESULTS The iMDSCs and tMDSCs significantly inhibited T cell proliferation in vitro and significantly prolonged corneal allograft survival in vivo. Strikingly, iMDSC transferring significantly reduced neovascularization that was comparable to transferring of tMDSCs, without additional immunosuppression. However, additional adoptive transfer of MDSCs did not further ameliorate corneal survival in these allogeneic corneal transplantation mice. CONCLUSIONS Inflammation-induced MDSC transfer could reduce corneal neovascularization and prolong corneal allograft survival.
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Affiliation(s)
- Yan He
- 1 Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmic and Visual Science Key Laboratory, Beijing, China. 2 Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Eye institute of The Second Xiangya Hospital of Central South University, Changsha, China. 3 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China. 4 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
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Zhao J, Li Z, Wang L, Liu J, Wang D, Chen G, Wang Q, Zhang H. Foxp3-expressing sensitized Teff cells prolong survival of corneal allograft in corneal allograft transplantation mouse model. Transpl Immunol 2015; 33:192-7. [PMID: 26419203 DOI: 10.1016/j.trim.2015.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 09/15/2015] [Accepted: 09/22/2015] [Indexed: 01/31/2023]
Abstract
OBJECTIVE The study aimed to investigate whether Foxp3-expressing sensitized Teff cells could inhibit allograft rejection in corneal allograft transplantation mouse model. METHODS Foxp3-expressing sensitized Teff cells were constructed by transfection of retroviral expression plasmid expressing Foxp3 into the sensi-Teff cells from a Balb/c mouse immunized by C57BL/6(H2b) mouse splenocytes. Balb/c mice were randomly divided into 5 groups: Four groups received tail vein injection of Foxp3-expressing sensitized Teff cells, or Foxp3-expressing Teff cells, or Treg cells or no intervention 1 day prior to corneal allograft transplantation. C57BL/6(H2b) was the donor mouse. The last group received corneal autograft transplantation. Corneal allograft survival time and percentage of CD4(+) T cells were detected. ELISPOT and Footpad swelling test were used to measure IL-2 and IFN-γ, and delayed-type hypersensitivity (DTH) response, respectively. RESULTS Mice that had received an injection of Foxp3-expressing sensitized T cells prior to an allograft corneal transplantation, showed significantly longer survival time of corneal allograft, decreased percentage of CD4(+) T cells, IL-2 and IFN-γ, and alleviated footpad swelling than the mice that had received either Foxp3-Teff or Treg cells. CONCLUSION Foxp3-sensi-Teff cell treatment that prolongs corneal allograft survival in the mouse model, might partly through suppressing CD4(+) T cells, IL-2 and IFN-γ.
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Affiliation(s)
- Jun Zhao
- Department of Ophthalmology, The 2nd Hospital of Shandong University, Jinan 250031, China; Department of Ophthalmology, General Hospital of Liaohe Oil Field, Panjin 124000, China
| | - Zhaohui Li
- The General Hospital of PLA, Beijing 100853, China
| | - Lei Wang
- Department of Ophthalmology, The 2nd Hospital of Shandong University, Jinan 250031, China
| | - Jing Liu
- Department of Ophthalmology, The 2nd Hospital of Shandong University, Jinan 250031, China
| | - Dajiang Wang
- The General Hospital of PLA, Beijing 100853, China
| | - Guoling Chen
- Department of Ophthalmology, The 2nd Hospital of Shandong University, Jinan 250031, China
| | - Qi Wang
- Department of Ophthalmology, General Hospital of Liaohe Oil Field, Panjin 124000, China
| | - Han Zhang
- Department of Ophthalmology, The 2nd Hospital of Shandong University, Jinan 250031, China.
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11
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Yin XT, Tajfirouz DA, Stuart PM. Murine corneal transplantation: a model to study the most common form of solid organ transplantation. J Vis Exp 2014:e51830. [PMID: 25490741 DOI: 10.3791/51830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Corneal transplantation is the most common form of organ transplantation in the United States with between 45,000 and 55,000 procedures performed each year. While several animal models exist for this procedure and mice are the species that is most commonly used. The reasons for using mice are the relative cost of using this species, the existence of many genetically defined strains that allow for the study of immune responses, and the existence of an extensive array of reagents that can be used to further define responses in this species. This model has been used to define factors in the cornea that are responsible for the relative immune privilege status of this tissue that enables corneal allografts to survive acute rejection in the absence of immunosuppressive therapy. It has also been used to define those factors that are most important in rejection of such allografts. Consequently, much of what we know concerning mechanisms of both corneal allograft acceptance and rejection are due to studies using a murine model of corneal transplantation. In addition to describing a model for acute corneal allograft rejection, we also present for the first time a model of late-term corneal allograft rejection.
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12
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Antigen-specific CD8 T cells can eliminate antigen-bearing keratinocytes with clonogenic potential via an IFN-gamma-dependent mechanism. J Invest Dermatol 2010; 130:1841-8. [PMID: 20237491 DOI: 10.1038/jid.2010.49] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The immune system surveys the skin for keratinocytes (KCs) infected by viruses or with acquired genetic damage. The mechanism by which T cells mediate KC elimination is however undefined. In this study we show that antigen-specific CD8 T cells can eliminate antigen-bearing KCs in vivo and inhibit their clonogenic potential in vitro, independently of the effector molecules perforin and Fas-ligand (Fas-L). In contrast, IFN-gamma receptor expression on KCs and T cells producing IFN-gamma are each necessary and sufficient for in vitro inhibition of KC clonogenic potential. Thus, antigen-specific cytotoxic T lymphocytes (CTLs) may mediate destruction of epithelium expressing non-self antigen by eliminating KCs with potential for self-renewal through an IFN-gamma-dependent mechanism.
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13
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Jin Y, Chauhan SK, Saban DR, Dana R. Role of CCR7 in facilitating direct allosensitization and regulatory T-cell function in high-risk corneal transplantation. Invest Ophthalmol Vis Sci 2009; 51:816-21. [PMID: 19797201 DOI: 10.1167/iovs.09-3952] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Chemokine receptor 7 (CCR7) is a key homing molecule for immune cell trafficking, including corneal antigen-presenting cell (APC) migration from the inflamed cornea to draining lymph nodes (LNs). Here, the authors investigated the effect of CCR7-facilitated donor APC trafficking on allosensitization, regulatory T-cell (Treg) function, and graft survival in corneal transplantation. METHODS CCR7(-/-) or wild-type (WT) allogeneic corneal grafts were transplanted onto the neovascularized high-risk recipient beds. Two weeks later, the frequency of directly alloprimed host T cells was measured by the IFN-gamma ELISPOT assay. Treg function was tested by a coculture suppression assay and an IFN-gamma ELISPOT assay. Kaplan-Meier analysis was performed to evaluate graft survival. RESULTS The recipients of CCR7(-/-) grafts had fewer migrated donor APCs and lower frequency of IFN-gamma-producing T cells in the draining LNs. However, there was no statistically significant difference in transplant survival between recipients of CCR7(-/-) and those of WT grafts. Tregs from the CCR7(-/-) graft recipient group showed reduced regulatory potential for the suppression of proliferation of naive T cells and direct alloprimed T cells and expressed lower Foxp3 levels. In vitro studies confirmed that mature CCR7(+) major histocompatibility complex class II(+) CD86(+) graft-derived dendritic cells were critical for Treg function. CONCLUSIONS Not only is CCR7-mediated donor-derived APC trafficking to the draining LNs important in the initiation of host T-cell priming, it is crucial for Treg-mediated tolerance.
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Affiliation(s)
- Yiping Jin
- Schepens Eye Research Institute and the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA
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14
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Hamrah P, Haskova Z, Taylor AW, Zhang Q, Ksander BR, Dana MR. Local treatment with alpha-melanocyte stimulating hormone reduces corneal allorejection. Transplantation 2009; 88:180-7. [PMID: 19623012 PMCID: PMC2735785 DOI: 10.1097/tp.0b013e3181ac11ea] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Corneal grafting is by far the most common form of transplantation. Many grafts suffer from immune rejection and current therapies are associated with many side effects, requiring more effective and safe therapies. alpha-Melanocyte stimulating hormone (alpha-MSH) is a neuropeptide that suppresses host inflammatory defense mechanisms. The purpose of this study was to determine the role of local therapy with alpha-MSH on corneal allograft survival, and the mechanisms by which it may influence graft outcome. METHODS Orthotopic corneal transplantation was performed, with recipients receiving subconjunctival alpha-MSH or sham injections twice weekly. Grafts were followed up for 70 days, and graft inflammation/opacification was compared between the two groups in a masked fashion. Graft infiltration and ocular gene expression of select inflammatory cytokines was evaluated at different timepoints. Additionally, allospecific delayed-type hypersensitivity was compared among the groups 3 weeks posttransplantation. RESULTS Results showed a significant increase in corneal graft survival in alpha-MSH-treated recipients compared with controls. Although 75% of allografts in alpha-MSH-treated hosts survived at 70 days, 43% survived in controls (P=0.04). Graft infiltration studies demonstrated a significant decrease in the number of mononuclear and polymorphonuclear cells in alpha-MSH-treated mice compared with controls at days 7 and 14 after transplantation. Furthermore, allospecific delayed-type hypersensitivity and gene expression of interferon-gamma and interleukin-2 showed a significantly reduced expression in alpha-MSH-treated mice compared with controls. CONCLUSIONS This study provides for the first time, in vivo evidence that treatment with local alpha-MSH may significantly reduce allorejection of orthotopic transplants.
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Affiliation(s)
- Pedram Hamrah
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
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15
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Boisgérault F, Liu Y, Anosova N, Dana R, Benichou G. Differential roles of direct and indirect allorecognition pathways in the rejection of skin and corneal transplants. Transplantation 2009; 87:16-23. [PMID: 19136886 PMCID: PMC2698296 DOI: 10.1097/tp.0b013e318191b38b] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND It is generally accepted that all transplants are not rejected in the same fashion. However, the extrinsic and intrinsic factors that control the recognition and rejection of a particular allograft by the host are not well characterized. METHODS We compared the mechanisms underlying the response with donor antigens by T cells activated after transplantation of fully allogeneic skin and corneal grafts in mice. RESULTS In corneal-transplanted mice, the CD4+ T-cell response was exclusively mediated by T cells recognizing minor antigens in an indirect fashion and producing low levels of interleukin-2. In contrast, skin grafts elicited both direct and indirect CD4+ T-cell responses primarily directed to major histocompatibility complex antigens and characterized by high interleukin-2 levels. Although CD8+ T-cells producing gamma interferon were activated directly in both skin- and corneal-grafted mice, only CD8+ T cells from skin-transplanted mice mounted a cytotoxic response. Next, we investigated whether failure of corneal transplants to induce a CD4+ direct alloresponse is due to their poor immunogenicity or due to the site of placement (eye). We observed that corneas transplanted under the skin and splenocytes transplanted in the eye were both capable of inducing direct CD4+ T-cell alloreactivity. CONCLUSIONS This shows that failure of orthotopic corneal allotransplants to elicit a CD4+ T-cell direct alloresponse is associated with the combination of two factors, their low immunogenicity and the immune-privileged properties of the eye.
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Affiliation(s)
- Florence Boisgérault
- Cellular and Molecular Immunology Laboratory, Massachusetts General Hospital, Department of Surgery, Transplantation Unit, Harvard Medical School, Boston, MA
| | - Ying Liu
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA
| | - Nathalie Anosova
- Cellular and Molecular Immunology Laboratory, Massachusetts General Hospital, Department of Surgery, Transplantation Unit, Harvard Medical School, Boston, MA
| | - Reza Dana
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA
| | - Gilles Benichou
- Cellular and Molecular Immunology Laboratory, Massachusetts General Hospital, Department of Surgery, Transplantation Unit, Harvard Medical School, Boston, MA
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16
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Gelman AE, Okazaki M, Lai J, Kornfeld CG, Kreisel FH, Richardson SB, Sugimoto S, Tietjens JR, Patterson GA, Krupnick AS, Kreisel D. CD4+ T lymphocytes are not necessary for the acute rejection of vascularized mouse lung transplants. THE JOURNAL OF IMMUNOLOGY 2008; 180:4754-62. [PMID: 18354199 DOI: 10.4049/jimmunol.180.7.4754] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Acute rejection continues to present a major obstacle to successful lung transplantation. Although CD4(+) T lymphocytes are critical for the rejection of some solid organ grafts, the role of CD4(+) T cells in the rejection of lung allografts is largely unknown. In this study, we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4(+) T cell-mediated allorecognition pathways. CD4(+) T cell-independent rejection occurs in the absence of donor-derived graft-resident hematopoietic APCs. Furthermore, blockade of the CD28/B7 costimulatory pathways attenuates acute lung allograft rejection in the absence of CD4(+) T cells, but does not delay acute rejection when CD4(+) T cells are present. Our results provide new mechanistic insight into the acute rejection of lung allografts and highlight the importance of identifying differences in pathways that regulate the rejection of various organs.
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Affiliation(s)
- Andrew E Gelman
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St Louis, MO 63110, USA
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17
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Porrett PM, Lee MK, Lian MM, Wang J, Caton AJ, Deng S, Markmann JF, Moore DJ. A direct comparison of rejection by CD8 and CD4 T cells in a transgenic model of allotransplantation. Arch Immunol Ther Exp (Warsz) 2008; 56:193-200. [PMID: 18512028 PMCID: PMC2766493 DOI: 10.1007/s00005-008-0019-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Accepted: 01/08/2008] [Indexed: 11/25/2022]
Abstract
INTRODUCTION The relative contributions of CD4+ and CD8+ T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4+ and CD8+ lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. MATERIALS AND METHODS Clone 4 and TS1 mice possess MHC class I- and II-restricted CD8+ and CD4+ T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8+ and CD4+ T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. RESULTS As in the authors' CD4+ model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5 x 10(5) Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA+ grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4+ and CD8+ cells acquired effector function and proliferated with similar kinetics. CONCLUSIONS These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.
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Affiliation(s)
- Paige M. Porrett
- Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Major K. Lee
- Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Moh Moh Lian
- Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Jing Wang
- Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 USA
| | | | - Shaoping Deng
- Division of Surgery, Department of Transplantation, Mass. General Hospital, Boston, MA 02114 USA
| | - James F. Markmann
- Division of Surgery, Department of Transplantation, Mass. General Hospital, Boston, MA 02114 USA
| | - Daniel J. Moore
- Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 USA
- Harrison Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt Children’s Hospital, 2200 Children’s Way, 11136 Doctors’ Office Tower, Nashville, TN 37232-9170 USA
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18
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Zhong J, Hadis U, De Kluyver R, Leggatt GR, Fernando GJP, Frazer IH. TLR7 stimulation augments T effector-mediated rejection of skin expressing neo-self antigen in keratinocytes. Eur J Immunol 2008; 38:73-81. [PMID: 18157820 DOI: 10.1002/eji.200737599] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Immunotherapy generally fails to induce tumour regression in spontaneously arising tumours. Failure is attributed to both tumour-related factors and an ineffective immune response. As a model of tumour immunotherapy, without the confounding effects of potential tumour-determined mechanisms of immune evasion, we studied the requirements for rejection of skin grafts expressing a neo-self antigen in somatic cells and not in antigen-presenting cells. When antigen expression was restricted to somatic cells, both CD4(+) and CD8(+) effector cells were required for graft rejection. Although freshly placed grafts were spontaneously rejected, healed grafts established under the cover of T cell depletion were not rejected even after T cell numbers recovered to a level where freshly placed grafts on the same animal were rejected, suggesting that healed skin grafts expressing a neo-self antigen only in somatic cells could not be rejected by primed recipients with functional effector T cells. Local TLR7 ligation induced inflammatory responses and rejection of healed grafts exposed to the TLR agonist but did not induce rejection of untreated healed grafts on the same animal. Thus, local pro-inflammatory signalling via TLR7 can promote effector T cell function against skin cells displaying their nominal antigen.
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Affiliation(s)
- Jie Zhong
- Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
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Hattori T, Usui Y, Okunuki Y, Sonoda Y, Usui M, Takada E, Mizuguchi J, Yagita H, Okumura K, Akiba H, Takeuchi M. Blockade of the OX40 ligand prolongs corneal allograft survival. Eur J Immunol 2008; 37:3597-604. [PMID: 18022861 DOI: 10.1002/eji.200636975] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Although corneal transplantation is one of the most common tissue transplantations and is known to have a high graft acceptance rate, occasional corneal graft rejection remains a cause of blindness. OX40, a member of the TNF receptor superfamily, is expressed on activated T cells, and transmits a costimulatory signal by binding to OX40 ligand (OX40L) expressed on several cells with antigen-presenting functions. Using a blocking monoclonal antibody (mAb) against murine OX40L, we investigated the role of OX40 in a murine model of corneal transplantation. C3H/He mouse corneas were transplanted to BALB/c mice orthotopically. Administration of anti-OX40L mAb significantly reduced allograft rejection, and increased graft survival rate to 40% at 8 weeks after transplantation, while all corneas were rejected within 5 weeks in control IgG-treated mice. Similar reduced rejection was observed when wild-type donor corneas were transplanted to OX40L-deficient recipients. In vitro study revealed that the anti-OX40L mAb treatment reduced proliferative response and IFN-gamma production of draining lymph node cells in response to stimulation with donor alloantigen. These results demonstrate that OX40L blockade is effective for prolongation of corneal allograft survival by inhibiting recipient T cell activation.
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Affiliation(s)
- Takaaki Hattori
- Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan
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20
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J2 prolongs the corneal allograft survival through inhibition of the CD4+ T cell-mediated response in vivo. Transpl Immunol 2007; 18:130-7. [PMID: 18005857 DOI: 10.1016/j.trim.2007.05.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Accepted: 05/22/2007] [Indexed: 11/22/2022]
Abstract
In our previous report, we described a novel non-peptidic organic ligand of CD4 D1, designated J2, as a potential inhibitor of CD4 D1 and thus CD4-dependent T cell responses in vitro. In this work, we further used a murine model of corneal allograft rejection to determine its in vivo immunosuppressive activities. To mimic the situation in high-risk human eyes, the recipient mice corneas were all induced by intrastromal sutures to serve as neovascularized graft beds. J2 was administrated by mouth 3 h before transplantation and thereafter on consecutive 12 days. The results showed that J2 could significantly prolong the median survival time of the corneal allografts, compared to the untreated control group. And the subsequent functional assays, including T cell phenotype analysis, delayed-type hypersensitivity (DTH) and enzyme-linked immunospot (ELISPOT) assays revealed that the immunosuppressive activity of J2 was associated with its inhibitory effects on the CD4(+) T cells and these cells-mediated responses. All these results suggest that J2 is a potential lead for the development of new immunosuppressive agents to prevent the corneal allograft rejection.
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21
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Lepisto AJ, Frank GM, Xu M, Stuart PM, Hendricks RL. CD8 T cells mediate transient herpes stromal keratitis in CD4-deficient mice. Invest Ophthalmol Vis Sci 2006; 47:3400-9. [PMID: 16877409 PMCID: PMC2366973 DOI: 10.1167/iovs.05-0898] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE To evaluate the role of CD4(+) T cells in the development of murine herpes stromal keratitis (HSK). METHODS The corneas of wild-type (WT) BALB/c mice and three types of CD4-deficient BALB/c mice (CD4(-/-), CD4-depleted, CD4 and CD8 double-depleted) were infected with different doses of HSV-1 RE, and HSK incidence and severity were monitored. Corneal infiltrates were quantitatively and functionally assayed by flow cytometric analysis of individually digested diseased corneas and documented histologically. RESULTS At a relatively high infectious dose (1 x 10(5) pfu/cornea): (1) CD4-deficient and WT BALB/c mice had severe HSK with a similar incidence (80%-100%), whereas HSK did not develop in mice deficient in both CD4(+) and CD8(+) T cells; (2) neutrophils were the predominate leukocyte in the corneas of CD4-deficient and WT mice; (3) the corneas of WT mice had activated, HSV-1-specific CD4(+) T cells, but few if any CD8(+) T cells; (4) the corneas of CD4-deficient mice had activated, HSV-1-specific CD8(+) T cells; and (5) HSK in CD4-deficient mice was transient, showing loss of CD8(+) T cells at 2 to 3 weeks after infection (pi) followed by a loss of neutrophils. At a relatively low infectious dose of HSV-1 (10(3) pfu/cornea) severe HSK developed in 80% to 90% of WT mice, but in only 30% to 40% of CD4-deficient mice. CONCLUSIONS CD4(+) T cells preferentially mediate HSK, but, in their absence, a high infectious dose of HSV-1 can induce histologically similar but transient HSK that is mediated by CD8(+) T cells.
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Affiliation(s)
- Andrew J. Lepisto
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Gregory M. Frank
- Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Graduate Program in Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Min Xu
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Patrick M. Stuart
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri
- Department of Molecular Microbiology and Pathogenesis, Washington University School of Medicine, St. Louis, Missouri
| | - Robert L. Hendricks
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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Stuart PM, Yin X, Plambeck S, Pan F, Ferguson TA. The role of Fas ligand as an effector molecule in corneal graft rejection. Eur J Immunol 2005; 35:2591-7. [PMID: 16114107 DOI: 10.1002/eji.200425934] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Previous studies have shown that the expression of Fas ligand (FasL; CD95L) by donor corneas is critical to their survival when placed on allogeneic recipients. Since there have been reports that the cornea expresses Fas, we tested the idea that FasL on lymphoid cells could be an effector molecule during rejection episodes. When FasL defective BALB/c-gld mice were engrafted with allogeneic corneas, significantly more of these corneas were accepted than by normal BALB/c mice. However, this was not due to impaired FasL-mediated effector function in these mice as the allogeneic corneas did not express detectable Fas by Western blot or RT-PCR analysis. Furthermore, donor corneas without Fas were given no survival advantage, but were rejected similar to wild-type donor allogeneic corneas. Examination of the T cell compartment in gld mice revealed that these cells express higher levels of Fas and are more susceptible to Fas-mediated death than wild-type cells. These results indicate that FasL is not an effector molecule in corneal graft rejection and that gld mice show reduced graft rejection due to greater susceptibility of their T cells to Fas-mediated apoptosis.
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Affiliation(s)
- Patrick M Stuart
- Department of Ophthalmology and Visual Sciences, Washington University Medical School, St. Louis, MO 63110, USA.
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23
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Yamada J, Hamuro J, Sano Y, Maruyama K, Kinoshita S. Allogeneic Corneal Tolerance in Rodents with Long-Term Graft Survival. Transplantation 2005; 79:1362-9. [PMID: 15912105 DOI: 10.1097/01.tp.0000159869.55962.94] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Healthy C57BL/6 orthotopic corneal allografts in place for more than 8 weeks in BALB/c mice (acceptor8w+) can survive indefinitely due to active suppression of the donor-specific delayed-type hypersensitivity (DTH) response. This suggests a state of tolerance in the acceptor mice, however, the mechanism(s) underlying this acceptance remains to be demonstrated. We investigated the relationship between tolerance-induction and the DTH response using murine re-grafting models to explore the possibility of promoting allogeneic corneal regraft acceptance in high-risk graft beds. METHODS Acceptor8w+ BALB/c mice received C57BL/6- or C3H corneal regrafts onto the same eye. Re-grafting models were prepared by inducing corneal neovascularization in the graft beds of naive BALB/c mice 2 weeks before corneal allografting. These mice were intravenously (iv) injected with purified splenic T cells or T-cell-depleted splenocytes from acceptor8w+ mice at the time they received re-grafts of C57BL/6 corneas. We also iv injected acceptor8w+ splenocytes into mice bearing healthy primary corneal allografts for 4 weeks (acceptor4w) and assessed their DTH response to C57BL/6 alloantigen(s). In those experiments, acceptor4w mice received a C57BL/6 corneal regraft onto the same eye. RESULTS In all acceptor8w+ mice there was indefinite survival of C57BL/6-, but not of C3H regrafts. The iv injection of T cells, but not of T-cell-depleted populations, from acceptor8w+ splenocytes promoted allograft survival. Acceptor4w mice iv injected with acceptor8w+ splenocytes manifested a reduced C57BL/6-specific DTH response and the survival rate of C57BL/6 regrafts was increased from 0% to 87.5%. CONCLUSION As donor-specific T cells from acceptor8w+ mice induced prolonged regraft survival, we posit that the active suppression of DTH responses by T cells may have contributed to indefinite allogeneic regraft survival via the induction of corneal allograft tolerance.
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Affiliation(s)
- Jun Yamada
- Department of Ophthalmology, Meiji University of Oriental Medicine, Kyoto, Japan.
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Youssef AR, Otley C, Mathieson PW, Smith RM. Role of CD4+ and CD8+ T cells in murine skin and heart allograft rejection across different antigenic desparities. Transpl Immunol 2005; 13:297-304. [PMID: 15589743 DOI: 10.1016/j.trim.2004.10.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2004] [Accepted: 10/25/2004] [Indexed: 11/17/2022]
Abstract
The factors that influence the relative contribution of the T cell subsets to allograft rejection remain unclear. We compared skin and heart rejection in CD4 Knockout (KO), and CD8 KO mice across full-, minor-, and class II histocompatibility antigen (HA) mismatches. Skin allografts were rejected by either CD4+ or CD8+ T cells alone at any degree of antigenic mismatch. However, either the absence of CD4+ cells or a lesser degree of HA mismatch resulted in prolongation of graft survival. In contrast, fully allogeneic heart grafts were accepted in CD4 KO recipients, and minor HA mismatched heart grafts were accepted by both CD4 KO and CD8 KO mice. Thus, the T cell subsets required for allograft rejection are determined by the immunogenicity of the tissue transplanted. In the absence of CD8+ T cells, perforin and Fas ligand (FasL) but not granzyme B mRNA were detected in rejecting grafts. Thus, granzyme B is a CD8+ cytotoxic T lymphocyte (CTL)-specific effector molecule.
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Affiliation(s)
- Abdel-Rahman Youssef
- Academic Renal Unit, Southmead Hospital, University of Bristol, Bristol BS10 5NB, UK
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25
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Wang YL, Zhang YY, Li G, Tang ZQ, Zhou YL, Zhu ZJ, Yao Z. Correlation of CD95 and soluble CD95 expression with acute rejection status of liver transplantation. World J Gastroenterol 2005; 11:1700-4. [PMID: 15786554 PMCID: PMC4305958 DOI: 10.3748/wjg.v11.i11.1700] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the expression levels of soluble form of CD95, CD95 ligand (sCD95 and sCD95L, respectively) in plasma and CD95 expression on CD3+ cells in liver-transplanted recipients with acute rejection (AR).
METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 30 clinically liver transplanted recipients. CD95 expression on CD3+ cells was quantitatively measured by two-color fluorescence activated cell sorter (FACS) analysis. Lymphocyte surface phenotypes of CD4, CD8, CD16 and CD56 were determined by flow cytometry. Plasma levels of sCD95 and sCD95L were detected by Enzyme Linked-Immuno-Sorbent Assay (ELISA). The results were compared with that from normal healthy volunteers (n = 15 individuals).
RESULTS: FACS analysis showed that CD95 expression on CD3+ T cells was significantly increased in liver transplanted recipients with AR compared to that in stable recipients without rejection and infection or healthy individuals who did not undergo transplantation (18676.93±11588.34/molecule, 6848.20±1712.96/molecule, 6418.01±2001.95/molecule, respectively, P<0.01). Whereas no significant difference was seen between liver-transplanted stable recipients and healthy individuals. Furthermore, no significant differences were detected between each group with CD4/CD8 ratio or the percentage of CD16+56+ cells. Plasma levels of sCD95 were significantly higher in transplanted recipients with AR compared to that in stable recipients or healthy individuals (391.88±196.00, 201.37±30.30, 148.83±58.25 pg/mL, respectively, P<0.01). In contrast, the plasma levels of sCD95L in liver- transplanted recipients were not significantly different from that in healthy individuals.
CONCLUSION: The present results indicate that the increased CD95 expression on CD3+ cells and the increased levels of sCD95 in plasma may modify the immunological situation of the recipients after transplantation or represent the ongoing graft rejection.
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Affiliation(s)
- Yu-Liang Wang
- Tianjin Institute of Thrombosis and Hemostasis, Laboratory Center, Tianjin First Central Hospital, 24 FuKang Road, Tianjin 300192, China.
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Zhan Y, Brown LE, Deliyannis G, Seah S, Wijburg OL, Price J, Strugnell RA, O'Connell PJ, Lew AM. Responses against complex antigens in various models of CD4 T-cell deficiency: surprises from an anti-CD4 antibody transgenic mouse. Immunol Res 2005; 30:1-14. [PMID: 15258307 DOI: 10.1385/ir:30:1:001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The most common models of CD4 T-cell deficiency are mice exogenously injected with anti-CD4 antibody (Ab), CD4 knockout (CD4-/-) and major histocompatibility complex (MHC) class II knockout (class II-/-) mice. We recently described the anti-CD4 Ab transgenic mouse (GK) as an improved CD4 cell-deficient model. This review compares this new GK mouse model with the widely available class II-/- and CD4-/- mice, when exposed to complex antigens (foreign grafts and during bacterial or viral infection). We highlight here the cytometric and functional differences (including Ab isotype, viral or bacterial clearance, and graft survival) among these CD4 cell-deficient models. For example, whereas grafts are generally rejected in class II-/- and CD4-/- mice as quickly as in wild-type mice, they survive longer in GK mice. Also, CD4-/- mice produce IgG against both simple model and complex antigens, but class II-/- and GK mice produce small amounts of IgG2a against complex antigens but not simple model antigens. These differences harbinger the caveats in the use of these various mice.
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Affiliation(s)
- Yifan Zhan
- Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3050, Australia
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Zhong J, Matsumoto K, De Kluyver R, Fernando GJ, Leggatt GR, Frazer IH. Human growth hormone presented by K14hGH‐transgenic skin grafts induces a strong immune response but no graft rejection. Immunol Cell Biol 2004; 82:577-86. [PMID: 15550115 DOI: 10.1111/j.1440-1711.2004.01292.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Although immune responses leading to rejection of transplantable tumours have been well studied, requirements for epithelial tumour rejection are unclear. Here, we use human growth hormone (hGH) expressed in epithelial cells (skin keratinocytes) as a model neo-self antigen to investigate the consequences of antigen presentation from epithelial cells. Mice transgenic for hGH driven from the keratin 14 promoter express hGH in skin keratinocytes. This hGH-transgenic skin is not rejected by syngeneic non-transgenic recipients, although an antibody response to hGH develops in grafted animals. Systemic immunization of graft recipients with hGH peptides, or local administration of stimulatory anti-CD40 antibody, induces temporary macroscopic graft inflammation, and an obvious dermal infiltrate of inflammatory cells, but not graft rejection. These results suggest that a neo-self antigen expressed in somatic cells in skin can induce an immune response that can be enhanced further by induction of specific immunity systemically or non-specific immunity locally. However, immune responses do not always lead to rejection, despite induction of local inflammatory changes. Therefore, in vitro immune responses and in vivo delayed type hypersensitivity are not surrogate markers for immune responses effective against epithelial cells expressing neoantigens.
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Affiliation(s)
- Jie Zhong
- Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
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28
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Huq S, Liu Y, Benichou G, Dana MR. Relevance of the Direct Pathway of Sensitization in Corneal Transplantation Is Dictated by the Graft Bed Microenvironment. THE JOURNAL OF IMMUNOLOGY 2004; 173:4464-9. [PMID: 15383577 DOI: 10.4049/jimmunol.173.7.4464] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Corneal grafts were until recently considered entirely devoid of resident APCs, giving rise to the tenet that alloantigen recognition is mediated exclusively by the indirect (host APC-dependent) pathway. The recent discovery of a resident myeloid corneal dendritic cell population that is normally MHC class II(-) but can readily up-regulate class II expression during inflammation led us to hypothesize that under certain conditions the direct pathway of allosensitization becomes operative. To test this, corneal allotransplants were performed in either inflamed (high-risk (HR)) or uninflamed (low-risk (LR)) host beds in mice, and the frequencies of host T cells activated via the direct pathway were determined. We found that directly primed CD4(+) T cells were detected in the HR but not LR setting, and these cells displayed a clear Th1 phenotype by 2 wk after grafting. Moreover, the use of MHC class II knockout donor tissue led to significantly enhanced survival of HR but not LR allografts. Finally, we show that donor corneal APC demonstrate high expression of CD40, CD80, and CD86 costimulatory molecules when derived from HR but not LR grafts. These data are the first to report that a functional donor APC-dependent direct response is elicited in corneal transplant hosts when the graft bed is inflamed and underscore the relevance of the graft microenvironment in dictating the pathway of allosensitization.
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Affiliation(s)
- Syed Huq
- Department of Ophthalmology, Schepens Eye Research Institute, Boston, MA 02114, USA
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29
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Stuart PM, Summers B, Morris JE, Morrison LA, Leib DA. CD8(+) T cells control corneal disease following ocular infection with herpes simplex virus type 1. J Gen Virol 2004; 85:2055-2063. [PMID: 15218191 DOI: 10.1099/vir.0.80049-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The role that T cell subsets play in herpetic stromal keratitis (HSK) has been the subject of intense research efforts. While most studies implicate CD4(+) T cells as the principal cell type mediating primary corneal disease, recent reports using knockout mice have suggested that both CD4(+) and CD8(+) T cell subsets may play integral roles in modulating the disease. Furthermore, recent studies suggest that CD8(+) T cells are directly involved in maintaining virus latency in infected trigeminal ganglia. This work has addressed these discrepancies by infecting the corneas of mice lacking CD4(+) and CD8(+) T cells with herpes simplex virus type 1 (HSV-1) and monitoring both corneal disease and latent infection of trigeminal ganglia. Results indicated that mice lacking CD8(+) T cells had more severe corneal disease than either BALB/c or B6 parental strains. In contrast, mice lacking CD4(+) T cells had a milder disease than parental strains. When mice were evaluated for persistence of infectious virus, only transient differences were observed in periocular tissue and corneas. No significant differences were found in persistence of virus in trigeminal ganglia or virus reactivation from explanted ganglia. These data support the following conclusions. CD4(+) T cells are not required for resistance to infection with HSV-1 and probably mediate HSK. Mice lacking CD8(+) T cells do not display differences in viral loads or reactivation and thus CD8(+) T cells are not absolutely required to maintain latency. Finally, CD8(+) T cells probably play a protective role by regulating the immunopathological response that mediates HSK.
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Affiliation(s)
- Patrick M Stuart
- Department of Molecular Microbiology & Pathogenesis, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
- Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
| | - Brett Summers
- Department of Molecular Microbiology & Pathogenesis, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
- Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
| | - Jessica E Morris
- Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
| | - Lynda A Morrison
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, MO 63104, USA
| | - David A Leib
- Department of Molecular Microbiology & Pathogenesis, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
- Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St Louis, MO 63110, USA
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30
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Ericson P, Lindén A, Riise GC. BAL levels of interleukin-18 do not change before or during acute rejection in lungtransplant recipients. Respir Med 2004; 98:159-63. [PMID: 14971880 DOI: 10.1016/j.rmed.2003.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
STUDY OBJECTIVE Acute rejection (AR) of the allograft is a major clinical problem after lungtransplantation. Repeated episodes of AR increase the risk of developing obliterative bronchiolitis, the main cause of mortality in this patient group. It is believed that AR is caused by T-lymphocytes reacting to donor antigens and in turn activating antigen presenting cells (APC) such as alveolar macrophages. Hypothetically, the interferon-gamma inducing cytokine IL-18 released from activated macrophages can play a role in the development of AR by modulating cytotoxic T-lymphocytes. DESIGN To determine whether IL-18 may serve as a marker of AR, we retrospectively analysed the concentration of soluble IL-18 protein and inflammatory cells in bronchoalveolar lavage fluid (BAL) from lungtransplant recipients. PATIENTS To minimize confounding factors, eight pairs of patients were matched for age, gender, pre-op diagnosis, type of operation, absence of infection and time post transplant. METHODS BAL levels of IL-18 (ELISA) and BAL cell differentials were analysed before, during and after an episode of AR and compared with the matched control group. CONCLUSION We found no changes in IL-18 concentration in BAL associated with AR. IL-18 in BAL did not correlate with BAL lymphocyte percentage. We conclude that change in soluble IL-18 protein does not constitute a useful marker of acute rejection in lung allograft recipients.
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Affiliation(s)
- Petrea Ericson
- Department of Respiratory Medicine & Allergology, Sahlgrenska Academy, University of Göteborg, Sweden
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31
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Abstract
BACKGROUND Second and subsequent corneal transplants in the same eye are more prone to rejection reactions and failure than first grafts. This may be a result of local changes or systemic sensitization to antigen shared by the first and second donors. Because HLA typing is not routine in corneal transplantation, a clear correlation between accelerated rejection and specific sensitization has not been established. METHODS PVG (RT1), Lewis (LEW; RT1), or AO (RT1) strain corneas were transplanted to PVG strain rats, followed by a LEW strain cornea in the ipsilateral or contralateral eye 6 weeks later. Graft survival was evaluated by slit lamp biomicroscopy. Proliferation of recipient lymph node cells was tested against allogeneic, syngeneic and third-party stimulator cells after the second transplantation. RESULTS A second allograft in the ipsilateral or contralateral eye was rejected in an accelerated fashion that was not donor MHC specific. Rejection was not significantly accelerated in the ipsilateral eye compared with the contralateral eye. There was a secondary lymphocyte proliferation response to third party (AO strain) in animals previously exposed only to the LEW strain. CONCLUSIONS Systemic sensitization to donor antigens, rather than local changes induced by first transplantation, contributed to accelerated rejection of a second graft. Accelerated rejection is not dependent on MHC compatibility between the grafts. It could be caused by shared "public" MHC determinants, by minor antigens shared by the first and second donors, or by cross-reactivity of T cells to epitopes on AO and LEW grafts. HLA mismatching of first and second donors may not prolong second graft survival.
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Affiliation(s)
- Sanjiv Banerjee
- Division of Ophthalmology, School of Medical Sciences, University Walk, Bristol, UK.
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32
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Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 2004; 3:879-89. [PMID: 14668804 DOI: 10.1038/nri1224] [Citation(s) in RCA: 539] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- J Wayne Streilein
- Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
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Haskova Z, Sproule TJ, Roopenian DC, Ksander ABR. An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection. Transplantation 2003; 75:1368-74. [PMID: 12717232 DOI: 10.1097/01.tp.0000063708.26443.3b] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Murine orthotopic corneal allografts experience immune privilege and have good survival as compared with skin allografts. However, privilege is not complete, and some grafts are still rejected. Unexpectedly, corneas expressing minor histocompatibility (H) alloantigens are rejected at a higher rate than major histocompatibility complex (MHC) disparate grafts. We hypothesize that certain immunodominant minor H alloantigens are extremely immunogenic when expressed in corneal tissue, terminate ocular immune privilege, and initiate corneal allograft rejection. METHODS AND RESULTS Corneal allograft survival and the role of CD4+ T cells and CD8+ T cells were examined in corneal transplants that expressed genetically defined minor H3 alloantigens. The H3 locus contains at least two minor H genes. H3a is presented by MHC class I and recognized exclusively by CD8+ T cells. H3b is presented by class II and recognized exclusively by CD4+ T cells. Congenic strains that differ from C57BL/10 at (1) H3a, (2) H3b, or (3) H3a+H3b were used for orthotopic corneal and skin transplants. Donor corneas expressing either H3a or H3a+H3b experienced immune privilege and survived longer than skin allografts. By contrast, donor corneas expressing H3b (recognized by CD4+ T cells) experienced vigorous rejection and were eliminated faster than skin allografts. CONCLUSION There are minor H alloantigens that terminate ocular immune privilege and initiate corneal allograft rejection. These minor H alloantigens are more immunogenic when expressed in corneal tissue than when they are expressed in skin allografts.
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Affiliation(s)
- Zdenka Haskova
- The Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
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34
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Abstract
Organ transplantation can be considered as replacement therapy for patients with end-stage organ failure. The percent of one-year allograft survival has increased due, among other factors, to a better understanding of the rejection process and new immunosuppressive drugs. Immunosuppressive therapy used in transplantation prevents activation and proliferation of alloreactive T lymphocytes, although not fully preventing chronic rejection. Recognition by recipient T cells of alloantigens expressed by donor tissues initiates immune destruction of allogeneic transplants. However, there is controversy concerning the relative contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models indicate that there is an absolute requirement for CD4+ T cells in allogeneic rejection, whereas in others CD4-depleted mice reject certain types of allografts. Moreover, there is evidence that CD8+ T cells are more resistant to immunotherapy and tolerance induction protocols. An intense focal infiltration of mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in patients. This suggests that CD8+ T cells could escape from immunosuppression and participate in the rejection process. Our group is primarily interested in the immune mechanisms involved in allograft rejection. Thus, we believe that a better understanding of the role of CD8+ T cells in allograft rejection could indicate new targets for immunotherapy in transplantation. Therefore, the objective of the present review was to focus on the role of the CD8+ T cell population in the rejection of allogeneic tissue.
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Affiliation(s)
- V Bueno
- Disciplina de Nefrologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.
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35
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Qian Y, Dana MR. Effect of locally administered anti-CD154 (CD40 ligand) monoclonal antibody on survival of allogeneic corneal transplants. Cornea 2002; 21:592-7. [PMID: 12131037 DOI: 10.1097/00003226-200208000-00012] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To determine the effect of ocular administration of anti-CD154 monoclonal antibody on the survival of orthotopic murine corneal transplants. METHODS BALB/c mice were used as recipients of multiple minor H- and MHC-mismatched orthotopic corneal transplants. Recipient beds were either avascular (normal-risk) or neovascularized (high-risk) at the time of surgery. Mice were randomized to receive either anti-CD154 antibody or control immunoglobulin by subconjunctival injection. All grafts were evaluated for signs of rejection by slitlamp biomicroscopy until week 20-24 with the therapy tapered and discontinued after week 8 and week 12, respectively. RESULTS In normal-risk transplantation, the 8-week survival rate improved from 30% in control mice to 90% in anti-CD154 treated mice (p= 0.0061). In high-risk transplantation, the survival rate of anti-CD154-treated mice was enhanced to 55% compared with 0% in control mice at week 8 (p= 0.0184); however, tapering and termination of anti-CD154 led to some loss in graft survival, with a survival rate of 56% in normal-risk recipients, and 22% in high-risk recipients by week 20. Anti-CD40L treated animals displayed lower grades of postoperative corneal neovascularization (p<0.05), in particular in normal-risk recipients. CONCLUSIONS Local ocular administration of anti-CD154 is effective in the prevention of corneal allograft rejection in normal-risk recipients, and in delaying the incidence of rejection in high-risk recipients. Long-term graft survival may not be fully achieved following termination of the CD40-CD154 pathway blockade.
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Affiliation(s)
- Ying Qian
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, U.S.A
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36
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Keadle TL, Morrison LA, Morris JL, Pepose JS, Stuart PM. Therapeutic immunization with a virion host shutoff-defective, replication-incompetent herpes simplex virus type 1 strain limits recurrent herpetic ocular infection. J Virol 2002; 76:3615-25. [PMID: 11907201 PMCID: PMC136075 DOI: 10.1128/jvi.76.8.3615-3625.2002] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Immunization of mice with herpes simplex virus type 1 (HSV-1) mutant viruses containing deletions in the gene for virion host shutoff (vhs) protein diminishes primary and recurrent corneal infection with wild-type HSV-1. vhs mutant viruses are severely attenuated in vivo but establish latent infections in sensory neurons. A safer HSV-1 mutant vaccine strain, Delta41Delta29, has combined vhs and replication (ICP8-) deficits and protects BALB/c mice against primary corneal infection equivalent to a vhs- strain (BGS41). Here, we tested the hypothesis that Delta41Delta29 can protect as well as BGS41 in a therapeutic setting. Because immune response induction varies with the mouse and virus strains studied, we first determined the effect of prophylactic Delta41Delta29 vaccination on primary ocular infection of NIH inbred mice with HSV-1 McKrae, a model system used to evaluate therapeutic vaccines. In a dose-dependent fashion, prophylactic Delta41Delta29 vaccination decreased postchallenge tear film virus titers and ocular disease incidence and severity while eliciting high levels of HSV-specific antibodies. Adoptive transfer studies demonstrated a dominant role for immune serum and a lesser role for immune cells in mediating prophylactic protection. Therapeutically, vaccination with Delta41Delta29 effectively reduced the incidence of UV-B-induced recurrent virus shedding in latently infected mice. Therapeutic Delta41Delta29 and BGS41 vaccination decreased corneal opacity and delayed-type hypersensitivity responses while elevating antibody titers, compared to controls. These data indicate that replication is not a prerequisite for generation of therapeutic immunity by live HSV mutant virus vaccines and raise the possibility that genetically tailored replication-defective viruses may make effective and safe therapeutic vaccines.
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Affiliation(s)
- Tammie L Keadle
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri 63110, USA
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Plsková J, Kuffová L, Holán V, Filipec M, Forrester JV. Evaluation of corneal graft rejection in a mouse model. Br J Ophthalmol 2002; 86:108-13. [PMID: 11801514 PMCID: PMC1770977 DOI: 10.1136/bjo.86.1.108] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Corneal graft rejection presents clinically and in experimental models as opacification and is considered to be the result of endothelial cell dysfunction or loss. However, recovery from opacification can occur suggesting either (a) that new endothelial cells can regenerate if the original cells were lost, or (b) that sufficient numbers of original cells can regain function if the opacification was due to temporary dysfunction. In this perspective, previous experimental studies of allograft rejection plus some new data are reviewed to support the latter mechanism.
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Affiliation(s)
- J Plsková
- Department of Ophthalmology, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK
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38
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Boisgérault F, Liu Y, Anosova N, Ehrlich E, Dana MR, Benichou G. Role of CD4+ and CD8+ T cells in allorecognition: lessons from corneal transplantation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 167:1891-9. [PMID: 11489968 DOI: 10.4049/jimmunol.167.4.1891] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-gamma-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.
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Affiliation(s)
- F Boisgérault
- Cellular and Molecular Immunology Laboratory, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
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Holán V, Zajícová A, Krulová M, Plsková J, Fric J, Filipec M. Induction of specific transplantation immunity by oral immunization with allogeneic cells. Immunology 2000; 101:404-11. [PMID: 11106945 PMCID: PMC2327093 DOI: 10.1046/j.1365-2567.2000.00111.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Oral administration of antigen has been shown to be effective for both positive and negative modulation of immune responses. In the present study we characterized changes in the reactivity of the immune system after oral immunization with allogeneic spleen cells. Mice were orally immunized for 10 consecutive days with fresh allogeneic spleen cells, and the phenotype, proliferative response, cytotoxic activity and cytokine production profile of recipient spleen cells were assessed 1 or 7 days after the last immunization dose. Although no significant changes in the proportion of CD4+, CD8+ or CD25+ cells were observed in the spleen of orally immunized mice, significant activation of alloreactivity in spleen cells was found. Cells from orally immunized mice exhibited enhanced proliferation and cytotoxic activity after stimulation with specific allogeneic cells in vitro, and produced considerably higher concentrations of interferon-gamma (IFN-gamma) and significantly less interleukin (IL)-4 than did cells from control mice. The production of IL-2 was essentially unchanged and that of IL-10 was only slightly increased. The systemic allosensitization induced by oral immunization was demonstrated in vivo by increased resistance to the growth of allogeneic tumours induced by subcutaneous inoculation of high doses of tumour cells. In addition, orthotopic corneal allografts in orally immunized recipients were rejected more rapidly (in a second-set manner) than in control, untreated recipients. These data show that oral immunization with allogeneic cells modulates individual components of the immune response and that specific transplantation immunity, rather than tolerance, is induced in the treated recipients.
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Affiliation(s)
- V Holán
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Faculty of Natural Sciences, Charles University, Prague, Department of Ophthalmology, Charles University, Prague, Czech Republic
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