• Humans
• Graft Rejection/immunology
• T-Lymphocytes/immunology
• Animals
• Transplantation, Homologous
• Antigen-Presenting Cells/immunology
• Histocompatibility Antigens/immunology

• Humans
• Autoimmunity
• T-Lymphocytes, Helper-Inducer
• Antigens
• B-Lymphocytes
• Autoimmune Diseases

• K08 DK120868 NIDDK NIH HHS
• U19 AI110495 NIAID NIH HHS

• T-Lymphocytes
• Graft Rejection
• Isoantigens
• Transplantation, Homologous
• Histocompatibility Antigens
• Proteins
• Allografts

• R01 DK115618 NIDDK NIH HHS

Previous studies indicated that mesenchymal stem cells (MSCs) exhibit immunomodulatory properties in composite tissue allotransplantation. However, due to the high immunogenicity of skin, although the single administration of MSCs improves survival of the skin allotransplant, immune rejection is still inevitable. The aim of our study was to evaluate whether multiple administrations of MSCs would improve immune tolerance in the allogeneic skin graft, compared to that with a single administration in a mouse model. After full-thickness skin allotransplantation on the backs of the mice, the recipient mice were infused with phosphate-buffered saline and isogenic 1.5 × 10⁵/mL adipose-derived stem cells (ADSCs). ADSCs were transplanted into different mice according to the different injection frequencies such as single, once a week, and twice a week. Skin sections were taken on days 7 and 21 post-transplantation in all groups for gene expression and histological studies. ADSCs increased skin allograft survival compared to that in control mice (P < 0.05). Interleukin-6 and tumor necrosis factor-alpha messenger RNA levels were decreased, and the abundance of lymphocytes, based on immunohistochemistry, was also decreased in ADSC-infused mice (P < 0.05). However, among the different ADSC injection frequency groups, multiple ADSC infusion did not improve the survival rate and decreased proinflammatory cytokines and lymphocytes, compared to those with the single administration of ADSCs (P > 0.05). Conversely, the results with single administration were slightly better than those with multiple administrations. Our study demonstrated that ADSCs have the potential for immunomodulation in vivo. However, the results with multiple ADSC administration were not as good as those with single administration, which indicates the complexity of ADSCs in vivo and implying the need for adequate preclinical experimentation.

• adipose-derived stem cells (ADSCs)
• allogenic skin graft
• anti-inflammation
• immunomodulation

• HLA-specific memory
• T cell-mediated rejection (TCMR)
• alloantibodies
• alloimmune response
• antibody-mediated rejection (ABMR)

• Chronic diseases
• Kauffman’s self-organization
• Neointimal formation
• Pattern of organ remodeling
• Unifying hypothesis

• C1q
• alloimmunity
• anaphylatoxins
• cancer
• hypertension
• neuroinflammation

• Allografts
• Exosomes
• Rejection
• tolerance

The success of tissue transplantation from a healthy donor to a diseased individual (allo-transplantation) is regulated by the immune systems of both donor and recipient. Developing a state of specific non-reactivity between donor and recipient, while maintaining the salutary effects of immune function in the recipient, is called “immune (transplantation) tolerance”. In the classic early post-transplant period, minimizing bidirectional donor ←→ recipient reactivity requires the administration of immunosuppressive drugs, which have deleterious side effects (severe immunodeficiency, opportunistic infections, and neoplasia, in addition to drug-specific reactions and organ toxicities). Inducing immune tolerance directly through donor and recipient immune cells, particularly via subsets of immune regulatory cells, has helped to significantly reduce side effects associated with multiple immunosuppressive drugs after allo-transplantation. The innate and adaptive arms of the immune system are both implicated in inducing immune tolerance. In the present article, we will review innate immune subset manipulations and their potential applications in hematopoietic stem cell transplantation (HSCT) to cure malignant and non-malignant hematological disorders by inducing long-lasting donor ←→ recipient (bidirectional) immune tolerance and reduced graft-versus-host disease (GVHD). These innate immunotherapeutic strategies to promote long-term immune allo-transplant tolerance include myeloid-derived suppressor cells (MDSCs), regulatory macrophages, tolerogenic dendritic cells (tDCs), Natural Killer (NK) cells, invariant Natural Killer T (iNKT) cells, gamma delta T (γδ-T) cells and mesenchymal stromal cells (MSCs).

• Graft-versus-Host Disease
• Innate immune cells
• allo-transplantation
• central tolerance
• immunosuppression
• mixed chimerism
• peripheral tolerance
• regulatory T Cells
• rejection
• thymic selection

• T cell allorecognition
• T follicular helper cell
• chronic allograft vasculopathy
• cytotoxic CD8 T cells
• exhaustion
• germinal center
• indirect presentation
• transplantation

• BP180
• antigen
• autoantibody
• desmoglein
• epitope
• epitope spreading
• pathogenesis
• specific therapy

• Autoantibodies/immunology
• Autoantigens/immunology
• Autoimmune Diseases/immunology
• Epitopes/immunology
• Humans
• Skin Diseases, Vesiculobullous/immunology

• Allele groups
• Genotype
• Haplotype
• Human Leukocyte Antigens (HLA)
• Major Histocompatibility Complex (MHC)

• Adaptive immunity
• Graft tolerance
• Immune rejection
• Inflammation
• Innate immunity
• Transplant immunology

B lymphocytes contribute to acute and chronic allograft rejection through their production of donor-specific antibodies (DSAs). In addition, B cells present allopeptides bound to self-MHC class II molecules and provide costimulation signals to T cells, which are essential to their activation and differentiation into memory T cells. On the other hand, both in laboratory rodents and patients, the concept of effector T cell regulation by B cells is gaining traction in the field of transplantation. Specifically, clinical trials using anti-CD20 monoclonal antibodies to deplete B cells and reverse DSA had a deleterious effect on rates of acute cellular rejection; a peculiar finding that calls into question a central paradigm in transplantation. Additional work in humans has characterized IL-10-producing B cells (IgM memory and transitional B cells), which suppress the proliferation and inflammatory cytokine productions of effector T cells in vitro. Understanding the mechanisms of regulating the alloresponse is critical if we are to achieve operational tolerance across transplantation. This review will focus on recent evidence in murine and human transplantation with respect to non-traditional roles for B cells in determining clinical outcomes.

• allorecognition
• antigen presentation
• autoimmune diseases
• regulatory B cells
• transplant rejection
• transplant tolerance

Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4⁺ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4⁺ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.

• B lymphocyte
• ELISPOT
• chronic allograft nephropathy
• indirect alloresponses
• interferon-γ

Autoimmune liver diseases (AILD) are rare diseases with a reported prevalence of less than 50 per 100 000 population. As the research landscape and our understanding of AILDs and liver transplantation evolves, there remain areas of unmet needs. One of these areas of unmet needs is prevention of disease recurrence after liver transplantation. Disease recurrence is not an insignificant event because allograft loss with the need for retransplantation can occur. Patients transplanted for AILD are more likely to experience acute rejection compared to those transplanted for non-AILD, and the reason(s) behind this observation is unclear. Tasks for the future include a better understanding of the pathogenesis of AILD, definition of the precise pathogenetic mechanisms of recurrent AILD, and development of strategies that can identify recipients at risk for disease recurrence. Importantly, the role of crosstalk between alloimmune responses and autoimmune responses in AILD is an important area that needs further study.

This article reviews the relevant literature of de novo autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis, and recurrent primary biliary cirrhosis in terms of the clinical entity, the scientific advancements, and future scientific goals to enhance our understanding of these diseases.

A review of the relevant literature of de novo autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis, and recurrent primary biliary cirrhosis in terms of the clinical entity, the scientific advancements and future scientific goals to enhance our understanding of these diseases.

• Acute rejection
• Adaptive immunity
• Biomarker
• Kidney transplantation
• MLR
• T and B cell ELISPOT

• Adaptive Immunity
• Animals
• Antigen Presentation/immunology
• CD4-Positive T-Lymphocytes/immunology
• Heart Transplantation
• Histocompatibility Antigens Class I/metabolism
• Immunity, Innate
• Isoantigens/immunology
• Lymphocyte Activation/immunology
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Peptides/immunology
• Transplantation, Homologous

• FS/10/018/28193 British Heart Foundation
• FS/12/87/29899 British Heart Foundation
• Wellcome Trust
• Department of Health

• Biomarker
• heart transplantation/cardiology
• monitoring: immune
• rejection: acute
• translational research/science
• vasculopathy

• drug targets
• rejection
• renal transplant

Human leukocyte Antigen (HLA) mismatching leads to severe complications after solid-organ transplantation and hematopoietic stem-cell transplantation. The alloreactive responses underlying the posttransplantation complications include both direct recognition of allogeneic HLA by HLA-specific alloantibodies and T cells and indirect T-cell recognition. However, the immunogenicity of HLA mismatches is highly variable; some HLA mismatches lead to severe clinical B-cell- and T-cell-mediated alloreactivity, whereas others are well tolerated. Definition of the permissibility of HLA mismatches prior to transplantation allows selection of donor-recipient combinations that will have a reduced chance to develop deleterious host-versus-graft responses after solid-organ transplantation and graft-versus-host responses after hematopoietic stem-cell transplantation. Therefore, several methods have been developed to predict permissible HLA-mismatch combinations. In this review we aim to give a comprehensive overview about the current knowledge regarding HLA-directed alloreactivity and several developed in vitro and in silico tools that aim to predict direct and indirect alloreactivity.

• Antibody-mediated rejection
• Donor-specific antibodies
• Epitopes
• Flow cytometry crossmatch
• Kidney transplantation

Current clinical strategies to control the alloimmune response after transplantation do not fully prevent induction of the immunological processes which lead to acute and chronic immune-mediated graft rejection, and as such the survival of a solid organ allograft is limited. Experimental research on naturally occurring CD4⁺CD25^highFoxP3⁺ Regulatory T cells (Tregs) has indicated their potential to establish stable long-term graft acceptance, with the promise of providing a more effective therapy for transplant recipients. Current approaches for clinical use are based on the infusion of freshly isolated or ex vivo polyclonally expanded Tregs into graft recipients with an aim to redress the in vivo balance of T effector cells to Tregs. However mounting evidence suggests that regulation of donor-specific immunity may be central to achieving immunological tolerance. Therefore, the next stages in optimizing translation of Tregs to organ transplantation will be through the refinement and development of donor alloantigen-specific Treg therapy. The altering kinetics and intensity of alloantigen presentation pathways and alloimmune priming following transplantation may indeed influence the specificity of the Treg required and the timing or frequency at which it needs to be administered. Here we review and discuss the relevance of antigen-specific regulation of alloreactivity by Tregs in experimental and clinical studies of tolerance and explore the concept of delivering an optimal Treg for the induction and maintenance phases of achieving transplantation tolerance.

• alloantigen
• antigen-specific
• direct pathway
• donor-specific
• indirect pathway
• linked suppression
• operational tolerance
• regulatory T cells

The existence of T-cell subsets naturally committed to perform immunoregulation has led to enthusiastic efforts to investigate their role in the immunopathogenesis of transplantation. Being able to modulate alloresponses, regulatory T cells could be used as an immunodiagnostic tool in clinical kidney transplantation. Thus, the measurement of Foxp3 transcripts, the presence of regulatory T cells in kidney biopsies, and the phenotypic characterisation of the T-cell infiltrate could aid in the diagnosis of rejection and the immune monitoring and prediction of outcomes in kidney transplantation. Interestingly, the adoptive transfer of regulatory T cells in animal models has been proven to downmodulate powerful alloresponses, igniting translational research on their potential use as an immunomodulatory therapy. For busy transplant clinicians, the vast amount of information in the literature on regulatory T cells can be overwhelming. This paper aims to highlight the most applicable research findings on the use of regulatory T cells in the immune diagnosis and potential immunomodulatory therapy of kidney transplant patients. However, can we yet rely on differential regulatory T-cell profiles for the identification of rejection or to tailor patient's immunosuppression? Are we ready to administer regulatory T cells as inductive or adjunctive therapy for kidney transplantation?