OKT3 therapy for the treatment of organ graft rejection is complicated by severe first dose side effects caused by T cell activation-induced cytokine release in vivo. Moreover, OKT3 causes pan-immunosuppression that can lead to increased infections and cancer. The investigators have developed a novel Fc receptor (FcR) non-binding form of anti-murine CD3 mAb, 2C11-IgG3, which suppresses immune responses in the absence of first dose side effects. In vitro, 2C11-IgG3 has short-lived effects on naive T cells, but delivers a partial signal to activated T cells that results in clonal inactivation of Th1 cells, proliferation/ cytokine production by Th2 cells, and Th2 deviation of undifferentiated T cells. Biochemical analyses of the early activation events in both T cell subsets show an identical pattern of partial phosphorylation of T cell receptor (TCR) zeta and ZAP-70 similar to that observed in T cells treated with altered CD4 receptor blockade during T cell activation. These results suggest that this novel TCR antagonist can differentially alter the intracellular signals that regulate Th1 and Th2 development selectively on antigen-experienced T cells. The investigators hypothesize that unbalanced biochemical signaling, exemplified by this mAb, is a common mechanism to regulate T cell differentiation and tolerance induction in vivo. The proposed study will focus on several questions: 1) Do the biochemical and functional changes induced by 2C11-IgG3 in vitro also occur in vivo in the allogeneic islet transplant model? 2) Can the mechanisms that regulate this process be defined? 3) What are the minimal biochemical signaling events required for Th cell differentiation? To answer these questions, the applicant proposes the following specific aims: 1) Determine the in vivo effect of 2C11-IgG3 mAb on T cell signaling in the allogeneic islet transplant model. 2) Use biochemical analyses and retroviral gene transfer to define the proximal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3. 3) Use biochemical analyses and retroviral gene transfer to define the distal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3.
| June, Carl H; Warshauer, Jeremy T; Bluestone, Jeffrey A (2017) Corrigendum: Is autoimmunity the Achilles' heel of cancer immunotherapy? Nat Med 23:1004 |
| Van Gool, Frédéric; Molofsky, Ari B; Morar, Malika M et al. (2014) Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood 124:3572-6 |
| Jeker, Lukas T; Bluestone, Jeffrey A (2013) MicroRNA regulation of T-cell differentiation and function. Immunol Rev 253:65-81 |
| Herold, Kevan C; Vignali, Dario A A; Cooke, Anne et al. (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243-56 |
| Wieland Brown, Laura C; Penaranda, Cristina; Kashyap, Purna C et al. (2013) Production of ?-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol 11:e1001610 |
| Bour-Jordan, Hélène; Thompson, Heather L; Giampaolo, Jennifer R et al. (2013) Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background. J Autoimmun 45:58-67 |
| Martínez-Llordella, Marc; Esensten, Jonathan H; Bailey-Bucktrout, Samantha L et al. (2013) CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response. J Exp Med 210:1603-19 |
| Penaranda, Cristina; Kuswanto, Wilson; Hofmann, Jerry et al. (2012) IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A 109:12668-73 |
| Tang, Qizhi; Bluestone, Jeffrey A; Kang, Sang-Mo (2012) CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol 4:11-21 |
| Brennan, Todd V; Tang, Qizhi; Liu, Feng-Chun et al. (2011) Requirements for prolongation of allograft survival with regulatory T cell infusion in lymphosufficient hosts. J Surg Res 169:e69-75 |
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