Inhibition of Interleukin 17 Significantly Attenuates the Severity of Autoimmune-Mediated Pathological Damage in Chronic Graft Versus Host Disease.

The evolution from acute GVHD which is mediated by alloreactive donor T cells to chronic GVHD which has prominent features of autoimmunity has long been an unresolved issue. Recently, we demonstrated that the progression from acute to chronic GVHD is due to the breaking of tolerance to self antigens. This is attributable to the progressive loss of CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells which results in the emergence of donor-derived T_H1 and T_H17 cells that are able to cause autoimmune-mediated pathological damage characterized by massive expansion of the innate immune system and release of proinflammatory cytokines (Chen et al, Blood, 2007, in press). While T_H1 cells have long been implicated in the pathogenesis of chronic GVHD, a putative role for T_H17 cells has not been previously described and the relative contribution of these cells to GVHD-associated autoimmunity is unknown. To address this question, we performed studies to determine the role of T_H17 cells in the pathophysiology of chronic GVHD. Lethally irradiated (900 cGy) Balb/c (H-2^d) mice were transplanted with either C57BL/6 (B6) (H-2^b) (allogeneic) or Balb/c (syngeneic) bone marrow plus spleen cells. Recipients of allogeneic marrow grafts had significantly higher levels of proinflammatory cytokines in the serum (e.g. IL-17, G-CSF, and IL-6) and increased numbers of T_H1 and T_H17 cells in the spleen compared to syngeneic controls, indicating that T_H17 cells emerged early post transplantation during the course of acute GVHD. Twenty days post transplantation, spleen cells from B6 → Balb chimeras undergoing acute GVHD were transferred into nonirradiated B6 Rag mice which results in the expansion of both T_H1 and T_H17 cells and the induction of autoimmune-mediated pathology (Chen et al, Blood, 2007). Cohorts of B6 Rag animals were then treated twice weekly for six weeks with either IL-17 monoclonal antibody (mAb) MM17F3 or control mouse IgG1 (0.2 mg/dose). Animals administered IL-17 mAb exhibited significantly less autoimmune-mediated weight loss than their control counterparts. Moreover, histological examination of liver, lung and colon tissues from these mice 60 days post transfer revealed significantly less pathology in IL-17 mAb-treated compared to control Ab-treated animals (pathology score 12 ± 0.6 versus 7.3 ± 1.2, p=0.025). The increase in splenic cellularity which is a hallmark of autoimmunity in this model was also significantly reduced in IL-17 mAb-treated mice (19.1 x 10⁶ versus 5.8 x 10⁶). There was no difference in the absolute number of CD4⁺ T cells or, more specifically, T_H17 cells in the spleen, liver or colon between the two cohorts of animals indicating that IL-17 antibody administration did not prevent the differentiation of T_H17 cells from naïve T_H0 precursors. Rather, protection was attributable to the inhibition of downstream IL-17-induced proinflammatory mediators and a corresponding reduction in cellular inflammation in tissue sites. These data demonstrate that the selective inhibition of IL-17 significantly attenuates the autoimmunity that occurs as a consequence of chronic GVHD. These studies establish IL-17 as a critical cytokine in the pathophysiology of GVHD and T_H17 cells as an important T cell population that mediates the progression from acute to chronic GVHD.