The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cellactivation, differentiation and effector/memory function, and in regulation of immune responses in auto-immunity and allergy/asthma. TIM-1 is expressed by activated Th1 and Th2 cells and its expression issustained preferentially in terminally differentiated Th2 cells. The ligand for TIM-1 is TIM-4, which ispredominantly expressed on APCs. Recent studies indicate that TIM-1 may differentially regulate T helper cell(Th1/Th2) differentiation in asthma/allergy, and autoimmune encephalomyelitis. At present, little is knownabout the role of the TIM-1 :TIM-4 pathway in alloimmune responses and autoimmune diabetes. Preliminarystudies from our group indicate that the TIM-1:TIM-4 pathway plays an important role in alloimmunity,particularly alloreactive T helper cell differentiation and possibly regulatory T cell generation/function.Furthermore, it is well established that the balance of autoreactive Th1 cells on one hand and regulatory Tcells and Th2 cells on the other is critical in determining the outcome of autoimmune diabetes in NOD mice.Our central hypothesis is that the TIM-1:TIM-4 pathway, by modulating Th1/Th2 cell differentiation andpossibly regulatory T cell generation and function, plays an important role in alloimmune and autoimmuneresponses, and tolerance. The main goal of this proposal is to define the functions and mechanisms of theTIM-1:TIM-4 pathway in regulating immune responses in vivo as a means of developing novel strategies toachieve durable and reproducible tolerance, and preventing the development of recurrent autoimmunity toislet allografts. In that regard, our approach is to test and explore the mechanisms of novel rationalcombination strategies that target multiple pathways resulting in silencing of alloreactive and autoreactive Tcells, and tipping the balance towards regulation by cells and/or cytokines in NOD recipients of islet allo-grafts.
In Specific Aim 1 we will investigate the effects of targeting the TIM-1 :TIM-4 pathway on alloimmuneand autoimmune responses in vivo in models of islet allograft rejection.
In Specific Aim 2 we will dissect themechanisms of action of TIM-1:TIM-4 pathway in alloimmunity, autoimmunity and tolerance, focusing on T cellexpansion, differentiation, and apoptosis. These studies will utilize CD4+ and CD8+ TCR transgenic animalswith defined allo- (B6 background) and auto- (NOD background) specificities. MHC tetramers will also beused to study the mechanisms of targeting TIM-1 on autoreactive CD4+ and CD8+ T cells in NOD mice.Finally, in Specific Aim 3 we will focus specifically on the role of TIM-1:TIM-4 pathway in the generationand/or function of regulatory T cells in vivo. Using foxp3-GFP knock-in reporter mice on B6 and NODbackgrounds, we will test the hypothesis, based on initial preliminary data, that the TIM-1:TIM-4 pathwaymayhave an important role in the generation and/or function of CD4+CD25+ regulatory T cells in vivo.Overall, our studies shouldyield useful new data that maylead to development of novel strategies toinduce tolerance to islet alloarafts to translate to orimates and humans.
Showing the most recent 10 out of 123 publications
