Anti-Thymocyte Globulin Prevents Autoimmune Encephalomyelitis by Expanding Myelin Antigen Specific Foxp3+ Regulatory T Cells

Brigham and Women's Hospital, Boston, Massachusetts, United States
International Immunology (Impact Factor: 2.54). 09/2007; 19(8):1003-10. DOI: 10.1093/intimm/dxm078
Source: PubMed


The T cell-depleting polyclonal antibody, anti-thymocyte globulin (ATG) has long been used in organ transplantation to treat acute rejection episodes. More recently, it is also being used as part of an induction regimen to protect allografts. It has been proposed that ATG might deplete effector T cells (T-effs) while sparing regulatory T cells (T-regs). In order to test whether ATG is effective in autoimmune disease, we used Foxp3gfp 'knock-in' mice in combination with a myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) tetramer to study more closely the effect of ATG treatment on antigen-specific T cell responses in vivo during MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. ATG treatment enhanced the expansion of MOG-specific T-regs (CD4(+)Foxp3(+)) in MOG-immunized mice. T-effs were depleted, but on a single-cell basis, the effector function of residual T-effs was not compromised by ATG. Thus, ATG tipped the balance of T-effs and T-regs and skewed an auto-antigen-specific immune reaction from a pathogenic T cell response to a potentially protective T-reg response. In both acute and relapsing remitting disease models, ATG treatment resulted in the attenuation from EAE, both in a preventive and early therapeutic setting. We conclude that ATG treatment enforces the development of a dominant immunoregulatory environment which may be advantageous for the treatment of T cell-driven autoimmune diseases.

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Available from: Stephen D Miller, Jan 15, 2014
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    • "Anti-thymocyte globulin (ATG), trade name thymoglobulin®, has been employed for decades as an immune modulator for a variety of clinical indications. It is currently one of the most common immunosuppressive reagents used in allogeneic transplantation [1-3] and more recently, in the treatment of a variety of autoimmune disorders [4-8]. There is a common belief that ATG therapy functions through complement mediated depletion of mature T cells. "
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    ABSTRACT: Background ATG has been employed to deplete T cells in several immune-mediated conditions. However, whether ATG administration affects naïve and memory T cell differently is largely unknown. The context and purpose of the study In this study, we assessed how murine ATG therapy affected T cell subsets in NOD mice, based on their regulatory and naïve or memory phenotype, as well as its influence on antigen-specific immune responses. Results Peripheral blood CD4+ and CD8+ T cells post-ATG therapy declined to their lowest levels at day 3, while CD4+ T cells returned to normal levels more rapidly than CD8+ T cells. ATG therapy failed to eliminate antigen-primed T cells. CD4+ T cell responses post-ATG therapy skewed to T helper type 2 (Th2) and possibly IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) were less sensitive to ATG depletion and remained at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory T cell phenotype was significantly increased in ATG-treated animals. Conclusion ATG therapy may modulate antigen-specific immune responses through inducing memory-like regulatory T cells as well as other protective T cells such as Th2 and IL-10-producing Tr1 cells.
    BMC Immunology 12/2012; 13(1):70. DOI:10.1186/1471-2172-13-70 · 2.48 Impact Factor
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    • "Importantly, the ability to expand CD4+IL-10+FoxP3+ T-cells in vitro seemed to correlate with the outcome of gene transfer in terms of development of inhibitory antibodies to the cFIX transgene product, with the two non-IS dogs J03 and J62 showing no expansion of these cells. Whether IS contributes to the induction of this CD4+IL-10+FoxP3+ T-cells population is not clear; however, it should be noted that a similar phenomenon has been described in the past for other IS regimens.53 The identification of a population of CD4+IL-10+FoxP3+ T-cells has implications for the design of future studies in humans in which vectors are administered with concurrent immunosuppression, as interference with tolerance induction may lead to development of harmful immune responses to the transgene product.2 "
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    ABSTRACT: Muscle represents an attractive target tissue for adeno-associated virus (AAV) vector-mediated gene transfer for hemophilia B (HB). Experience with direct intramuscular (i.m.) administration of AAV vectors in humans showed that the approach is safe but fails to achieve therapeutic efficacy. Here, we present a careful evaluation of the safety profile (vector, transgene, and administration procedure) of peripheral transvenular administration of AAV-canine factor IX (cFIX) vectors to the muscle of HB dogs. Vector administration resulted in sustained therapeutic levels of cFIX expression. Although all animals developed a robust antibody response to the AAV capsid, no T-cell responses to the capsid antigen were detected by interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISpot). Interleukin (IL)-10 ELISpot screening of lymphocytes showed reactivity to cFIX-derived peptides, and restimulation of T cells in vitro in the presence of the identified cFIX epitopes resulted in the expansion of CD4(+)FoxP3(+)IL-10(+) T-cells. Vector administration was not associated with systemic inflammation, and vector spread to nontarget tissues was minimal. At the local level, limited levels of cell infiltrates were detected when the vector was administered intravascularly. In summary, this study in a large animal model of HB demonstrates that therapeutic levels of gene transfer can be safely achieved using a novel route of intravascular gene transfer to muscle.
    Molecular Therapy 07/2010; 18(7):1318-29. DOI:10.1038/mt.2010.73 · 6.23 Impact Factor
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    • "Existing and emerging therapies aimed at regulating the autoimmune response largely involve broad-based immunoregulatory strategies, including the inhibition or deletion of lymphocytes subsets and/or use of agents proposed to induce or re-establish immune tolerance via activation of regulatory T cells (Tregs), e.g. non-mitogenic anti-CD3 or antithymocyte globulin (Chatenoud, 2003; Chatenoud et al., 2001; Chung et al., 2007; Kohm et al., 2005). Some of these have shown efficacy in initial clinical trials, but there are risks with any of the broad approaches such as cytokine release and/or reactivation of latent viruses. "
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    ABSTRACT: Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by destruction of insulin-producing pancreatic beta cells. Many broad-based immunosuppressive and antigen-specific immunoregulatory therapies have been and are currently being evaluated for their utility in the prevention and treatment of T1D. Looking forward, this review discusses the potential therapeutic use of antigen-specific tolerance strategies, including tolerance induced by "tolerogenic" antigen-presenting cells pulsed with diabetogenic antigens and transfer of induced or expanded regulatory T cells, which have demonstrated efficacy in nonobese diabetic (NOD) mice. Depending on the time of therapeutic intervention in the T1D disease process, antigen-specific immunoregulatory strategies may be employed as monotherapies, or in combination with short-term tolerance-promoting immunoregulatory drugs and/or drugs promoting differentiation of insulin-producing beta cells from endogenous progenitors.
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