T cell vaccination therapy in an induced model of anti-RNP autoimmune glomerulonephritis

Trivedi, Sapna; Zang, Yunjuan; Culpepper, Schartess; Rosenbaum, Erica E.; Fernández, Irina; Martinez, Laisel; Hoffman, Robert W.; Greidinger, Eric L.

doi:10.1016/j.clim.2010.07.013

Cited by 6 publications

(16 citation statements)

References 18 publications

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“…Adoptive transfer of anti-RNP-specific CD4+ T cells is sufficient to transfer nephritis in mice and to induce spreading autoantibody production (6). Remarkably, T Cell Receptor Vbeta CDR3 region motifs are conserved in the anti-RNP T cells we observe in multiple human patients and in our mouse model (9,10). We therefore hypothesize that T cells expressing conserved CDR3 regions are pathogenic for anti-RNP autoimmunity and that T cell vaccination targeting this limited range of antigen-specific TCRs has the potential to be an effective immunotherapy.…”

Section: Introductionsupporting

confidence: 54%

“…Anti-RNP CD4+ T cells appear at high frequency (compared to healthy controls) in PBMC in SLE patients and in the spleen and lesional tissues of anti-RNP autoimmune mice (9,10). Adoptive transfer of anti-RNP-specific CD4+ T cells is sufficient to transfer nephritis in mice and to induce spreading autoantibody production (6).…”

Section: Introductionmentioning

confidence: 99%

“…Previous work has shown that treatments designed to target these anti-RNP T cells have been sufficient to induce significant clinical responses in both mice and humans (10,11). However, these prior studies have not established that the beneficial effects observed were related to effects on pathogenic anti-RNP T cells as opposed to nonspecific immunomodulatory effects.…”

Section: Introductionmentioning

confidence: 99%

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Conservation of Pathogenic TCR Homology across Class II Restrictions in Anti-Ribonucleoprotein Autoimmunity: Extended Efficacy of T Cell Vaccine Therapy

Zang

Martinez²,

Fernández

et al. 2014

The Journal of Immunology

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T cells have been shown to mediate aspects of anti-RNP autoimmunity, and are a potential target of therapy in lupus and related diseases. In this study, we assessed the relevance of a conserved class of anti-RNP T cells to autoimmune disease expression and therapy. Our data show that anti-RNP T cell selection induced a limited set of homologous CDR3 motifs at high frequency. Homologous CDR3 motifs have been reported in other autoimmune diseases. Vaccination with irradiated anti-RNP (but not anti-Tetanus Toxoid) CD4+ cells induced remission of anti-RNP-associated nephritis in at least 80% of treated mice, even with donor/recipient MHC Class II mismatch, and in both induced and spontaneous autoimmunity. Vaccine responder sera inhibited anti-70k T cell proliferation and bound hybridomas expressing the conserved CDR3 motifs. Our data indicate that a limited set of TCR CDR3 motifs may be important for the pathogenesis of anti-RNP lupus and other autoimmune diseases. The ability to target a consistent set of pathogenic T cells between individuals and across Class II restrictions may allow for the more practical development of a standardized anti-RNP T cell vaccine preparation useful for multiple patients.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conservation of Pathogenic TCR Homology across Class II Restrictions in Anti-Ribonucleoprotein Autoimmunity: Extended Efficacy of T Cell Vaccine Therapy

Zang

Martinez²,

Fernández

et al. 2014

The Journal of Immunology

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“…15 This finding has led to TCV in clinical trials in patients with multiple sclerosis. [16][17][18] In glomerulonephritis, the work by Trivedi et al 19 using an HLA DR4 transgenic humanized mouse model with peptide immunization has induced nephritis that is limited by TCV. However, the protection against disease in this model is limited by its variability.…”

mentioning

confidence: 99%

“…However, the protection against disease in this model is limited by its variability. 19 Human idiopathic membranous nephritis is an autoimmune renal disease characterized by severe proteinuria and progression to renal failure. 20 It is frequently caused by sensitization to phospholipase A2 receptor, an antigen expressed on glomerular podocytes, 21 and associated with antibody deposition in the glomerulus.…”

mentioning

confidence: 99%

CD8+ Regulatory T Cells Induced by T Cell Vaccination Protect Against Autoimmune Nephritis

Wang

Zhang

et al. 2012

Journal of the American Society of Nephrology

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Autoreactive T cells play a pivotal role in the pathogenesis of autoimmune kidney disease. T cell vaccination (TCV) may limit autoimmune disease and induce CD8+ regulatory T cells (Tregs). We used Heymann nephritis (HN), a rat model of human membranous nephritis, to study the effects of TCV on autoimmune kidney disease. We harvested CD4+ T cells from renal tubular antigen (Fx1A) -immunized rats and activated these cells in vitro to express the MHC Class Ib molecule Qa-1. Vaccination of Lewis rats with these autoreactive Fx1A-induced T cells protected against HN, whereas control-primed T cells did not. Rats that underwent TCV had lower levels of proteinuria and serum creatinine and significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates. Furthermore, these rats expressed less IFN-g and IL-6 in splenocytes, whereas the numbers of Tregs and the expression of Foxp3 were unchanged. In vitro cytotoxicity assays showed CD8+ T cell-mediated elimination of Qa-1-expressing CD4+ T cells. In vivo, TCV abrogated the increase in Qa-1-expressing CXCR5+ TFH cells observed in HN compared with controls. Taken together, these results suggest that TCV protects against autoimmune kidney disease by targeting Qa-1-expressing autoreactive CD4+ cells.

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The Mechanisms and Applications of T Cell Vaccination for Autoimmune Diseases: a Comprehensive Review

Huang

2014

Clinic Rev Allerg Immunol

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Autoimmune diseases (ADs) are a spectrum of diseases originating from loss of immunologic self-tolerance and T cell abnormal autoreactivity, causing organ damage and death. However, the pathogenic mechanism of ADs remains unclear. The current treatments of ADs include nonsteroidal anti-inflammatory drugs (NSAIDS), antimalarials, corticosteroids, immunosuppressive drugs, and biological therapies. With the need to prevent side effects resulting from current treatments and acquire better clinical remission, developing a novel pharmaceutical treatment is extremely urgent. The concept of T cell vaccination (TCV) has been raised as the finding that immunization with attenuated autoreactive T cells is capable of inducing T cell-dependent inhibition of autoimmune responses. TCV may act as an approach to control unwanted adaptive immune response through eliminating the autoreactive T cells. Over the past decades, the effect of TCV has been justified in several animal models of autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), murine autoimmune diabetes in nonobese diabetic (NOD) mice, collagen-induced arthritis (CIA), and so on. Meanwhile, clinical trials of TCV have confirmed the safety and efficacy in corresponding autoimmune diseases ranging from multiple sclerosis (MS) to systemic lupus erythematosus (SLE). This review aims to summarize the ongoing experimental and clinical trials and elucidate possible molecule mechanisms of TCV.

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T cell vaccination therapy in an induced model of anti-RNP autoimmune glomerulonephritis

Cited by 6 publications

References 18 publications

Conservation of Pathogenic TCR Homology across Class II Restrictions in Anti-Ribonucleoprotein Autoimmunity: Extended Efficacy of T Cell Vaccine Therapy

Conservation of Pathogenic TCR Homology across Class II Restrictions in Anti-Ribonucleoprotein Autoimmunity: Extended Efficacy of T Cell Vaccine Therapy

CD8+ Regulatory T Cells Induced by T Cell Vaccination Protect Against Autoimmune Nephritis

The Mechanisms and Applications of T Cell Vaccination for Autoimmune Diseases: a Comprehensive Review

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