• Anabasis articulate
• Arthritis
• adjuvant-induced arthritis
• vascular endothelial growth factor

• PG G1 domain-induced arthritis
• aggrecan)
• animal models
• anti-inflammatory
• collagen-induced arthritis
• cytokines
• immunotherapy
• inflammatory
• peptide vaccine
• proteo-glycan (PG
• rheumatoid arthritis

• R44 AR063504-02A1 NIAMS NIH HHS
• R43 AR063504 NIAMS NIH HHS
• R01 AR064206 NIAMS NIH HHS
• R01 AAR062991 NIAMS NIH HHS

• Food allergy
• Oral tolerance
• Ovalbumin
• Peanuts

• arthritis
• immunomodulation
• microscopy research
• oral tolerance
• vitamin D

• arthritis-specific antigens
• arthritogenic epitopes
• autoimmune disease
• bystander effect
• epitope spreading
• rheumatoid arthritis
• signature cytokine
• therapeutic vaccines

The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well.

EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG_35–55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG_35–55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset.

We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE.

• Adoptive Transfer
• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Cells, Cultured
• Central Nervous System/drug effects
• Central Nervous System/immunology
• Central Nervous System/pathology
• Chloroquine/pharmacology
• Chloroquine/therapeutic use
• Dendritic Cells/drug effects
• Dendritic Cells/immunology
• Encephalomyelitis, Autoimmune, Experimental/drug therapy
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Female
• Humans
• Immunologic Factors/pharmacology
• Immunologic Factors/therapeutic use
• Interferon-gamma/metabolism
• Interleukin-17/metabolism
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis/drug therapy
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/transplantation

• Heart failure
• Pain
• Palliative care
• Symptoms
• Therapy

Parenteral injection of tolerated proteins into orally tolerant mice inhibits the initiation of immunological responses to unrelated proteins and blocks severe chronic inflammatory reactions of immunological origin, such as autoimmune reactions. This inhibitory effect which we have called “indirect effects of oral tolerance” is also known as “bystander suppression.” Herein, we show that i.p. injection of OVA + Al(OH)₃ minutes before i.v. injection of Schistosoma mansoni eggs into OVA tolerant mice blocked the increase of pulmonary granulomas. In addition, the expression of ICAM-1 in lung parenchyma in areas outside the granulomas of OVA-orally tolerant mice was significantly reduced. However, at day 18 after granuloma induction there was no difference in immunofluorescency intensity to CD3, CD4, F4/80, andα-SMA per granuloma area of tolerant and control groups. Reduction of granulomas by reexposure to orally tolerated proteins was not correlated with a shift in Th-1/Th-2 cytokines in serum or lung tissue extract.

Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. A 24-week, double-blind, double-dummy, randomized, methotrexate (MTX)-controlled study was conducted to evaluate the efficacy and safety of CCII in the treatment of rheumatoid arthritis (RA).

Five hundred three RA patients were included in the study. Patients received either 0.1 mg daily of CCII (n = 326) or 10 mg once a week of MTX (n = 177) for 24 weeks. Each patient was evaluated for pain, morning stiffness, tender joint count, swollen joint count, health assessment questionnaire (HAQ), assessments by investigator and patient, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) by using the standard tools at baseline (week 0) and at weeks 12 and 24. Additionally, rheumatoid factor (RF) was evaluated at weeks 0 and 24. Measurement of a battery of biochemical parameters in serum, hematological parameters, and urine analysis was performed to evaluate the safety of CCII.

Four hundred fifty-four patients (94.43%) completed the 24-week follow-up. In both groups, there were decreases in pain, morning stiffness, tender joint count, swollen joint count, HAQ, and assessments by investigator and patient, and all differences were statistically significant. In the MTX group, ESR and CRP decreased. RF did not change in either group. At 24 weeks, 41.55% of patients in the CCII group and 57.86% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR-20) and 16.89% and 30.82%, respectively, met the ACR 50% improvement criteria (ACR-50). Both response rates for ACR-20 and ACR-50 in the CCII group were lower than those of the MTX group, and this difference was statistically significant (P < 0.05). The DAS28 (disease activity score using 28 joint counts) values of the two treatment groups were calculated, and there was a statistically significant difference between the two treatment groups (P < 0.05). Gastrointestinal complaints were common in both groups, but there were fewer and milder side effects in the CCII group than in the MTX group. The incidence of adverse events between the two groups was statistically significant (P < 0.05).

CCII is effective in the treatment of RA and is safe for human consumption. CCII exerts its beneficial effects by controlling inflammatory responses through inducing oral tolerance in RA patients.

Clinical trial registration number: ChiCTR-TRC-00000093.

• Animals
• Cell Proliferation
• Cells, Cultured
• Cytokines/biosynthesis
• Enzyme-Linked Immunosorbent Assay/methods
• Gene Expression Regulation/immunology
• Hypersensitivity, Delayed/immunology
• Immune Tolerance
• Immunity, Cellular
• Immunity, Mucosal
• Immunoglobulin A/blood
• Immunoglobulin A, Secretory/analysis
• Intestinal Mucosa/immunology
• Intestine, Small/immunology
• Male
• Mice
• Mice, Inbred C57BL
• Ovalbumin/immunology
• RNA, Messenger/genetics
• Receptors, Vasoactive Intestinal Peptide, Type II/metabolism
• Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism
• Spleen/immunology
• Vasoactive Intestinal Peptide/biosynthesis
• Vasoactive Intestinal Peptide/genetics
• Vasoactive Intestinal Peptide/immunology

• Administration, Oral
• Adoptive Transfer
• Animals
• Factor VIII/immunology
• Female
• Humans
• Immune Tolerance/drug effects
• Immunoglobulin Fab Fragments/pharmacology
• Immunoglobulin Fc Fragments/pharmacology
• Immunoglobulins, Intravenous/administration & dosage
• Immunoglobulins, Intravenous/pharmacology
• Mice
• Mice, Inbred BALB C
• Rheumatoid Factor/blood