Graft versus host disease (GVHD) is the major complication associated with allogeneic stem cell transplantation. GVHD is the result of a series of proinflammatory events that are attributable to the conditioning regimen in conjunction with the recognition of host alloantigens by donor T cells. This initiates an inflammatory cascade that is characterized by the expansion of alloreactive donor T cells, recruitment of secondary effector cell populations and production of proinflammatory cytokines. The gastrointestinal tract, in particular, has been demonstrated to be a critical target organ in GVHD pathophysiology. Translocation of lipopolysaccharide (LPS) across mucosal surfaces in the gastrointestinal tract that have been damaged by both the conditioning regimen and donor T cells has been shown to induce systemic proinflammatory cytokine production that plays a significant role in the propagation of pathological damage both locally and systemically. How mucosal damage and LPS leakage induces the wide spectrum of proinflammatory effects that occur during GVHD, however, is not completely understood. In preliminary studies, we have now identified interleukin (IL-23) as the critical mediator linking conditioning regimen-induced mucosal injury and LPS translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. We have also made the novel observation that, in the absence of donor APC-derived secretion of IL-23, the colon is selectively protected from developing acute GVHD. Thus, within the context of a multi system, inflammatory disorder our studies demonstrate that a single cytokine can be responsible for directing tissue-specific pathology. The goal of this proposal is to define how IL-23 mediates proinflammatory events and test novel strategies for the inhibition of IL-23 that may allow for a reduction in GVHD without loss of antileukemia effects conferred by the allogeneic graft. To address these questions, experiments have been designed to address the following specific aims: Studies in Specific Aim 1 will define the mechanism by which IL-23 mediates pathological damage in the colon. These studies will also define the optimal timing for the inhibition of IL-23 with respect to GVHD prevention.
Specific Aim 2 will examine the effect of IL-23 on the regulatory arm of the immune system. Using a unique model in which regulatory T cells can be precisely identified in vivo, we will define the role of IL-23 in the function and reconstitution of regulatory T cells (Tregs) after transplantation.
Specific Aim 3 will determine if the selective targeting of IL-23 can preserve the graft versus leukemia effect while at the same time reducing the severity of GVHD. The overall goal of these studies is to define the biological effects of IL-23 as they relate to both GVH and GVL reactivity after allogeneic stem cell transplantation.
The relevance of this project to public health derives from the fact that graft versus host disease is the major complication of allogeneic stem cell transplantation. Better understanding of how to reduce this complication while at the same time preserving the beneficial antileukemic effects that result from the transplant will lead to new therapies and better outcomes for patients.
|Chen, Xiao; Dodge, Joseph; Komorowski, Richard et al. (2013) A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease. Blood 121:3970-80|
|Rangarajan, Hemalatha; Yassai, Maryam; Subramanian, Hariharan et al. (2012) Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease. Blood 119:6354-64|
|Beres, Amy; Komorowski, Richard; Mihara, Masahiko et al. (2011) Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease. Clin Cancer Res 17:3969-83|
|Das, Rupali; Komorowski, Richard; Hessner, Martin J et al. (2010) Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood 115:5249-58|