GITR Blockade Facilitates Treg Mediated Allograft Survival.

Sonawane SB, Kim JI, Lee MK, Lee SH, Duff PE, Moore DJ, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF
Transplantation. 2009 88 (10): 1169-77

PMID: 19935370 · PMCID: PMC2803064 · DOI:10.1097/TP.0b013e3181ba6f85

BACKGROUND - Many models of transplant tolerance have been found to depend on the induction of regulatory T cells (Tregs). Innate immune signals are known to suppress Tregs thereby augmenting immunity by abrogating Treg function. Such signals may also provide a barrier to transplantation tolerance mediated by Tregs. A number of cell surface molecules expressed by Tregs have been found to inhibit Treg activity, the best characterized of which is the glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein.

METHODS - By using an adoptive transfer model of allograft rejection, we can study the effects of inflammation and antigen-specific Tregs on graft survival. Inflammation resulting from the transplant procedure counter-regulates the suppressor activity of Tregs. To assess whether Treg activity could be enhanced by blocking GITR signaling, we compared the capacity of Tregs to prolong the survival of grafts in the presence or absence of activation-inducible TNF receptor (AITRL)-Fc, a novel construct that binds GITR.

RESULTS - We report that interruption of GITR-GITR ligand (GITRL) binding by AITRL-Fc resulted in long-term Treg-dependent acceptance of skin grafts in the setting of innate immune signals that otherwise interfere with Treg activity.

CONCLUSIONS - Inflammation and other innate immune signals may activate antigen presenting cells to upregulate GITRL. GITR-GITRL interaction is one pathway by which antigen presenting cells may enhance the adaptive response to foreign antigen by counter-regulating Tregs and by costimulating effector T cells. By blocking this interaction with AITRL-Fc, one can sustain the benefit conferred by graft-protective Tregs.

MeSH Terms (22)

Animals CD4-Positive T-Lymphocytes Crosses, Genetic Epitopes Flow Cytometry Glucocorticoid-Induced TNFR-Related Protein Graft Survival Humans Immunosuppression Inflammation Lymphocytes Mice Mice, Inbred BALB C Mice, Transgenic Receptors, Nerve Growth Factor Receptors, Tumor Necrosis Factor Signal Transduction Skin Transplantation Survival Rate T-Lymphocytes, Regulatory Transplantation, Homologous Tumor Necrosis Factors

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