The upregulation ofCX3CL1mRNA in cytokine-treated human islets as well as in rodent models has been noted previously (9,16), but to date no protein expression analyses have been reported in the specific context of type 1 diabetes. of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies. The molecular determinants in the control of initiation, coordination, and perpetuation of innate and adaptive immune responses that together precipitate -cell destruction and eventual development of clinical type 1 Rabbit Polyclonal to MBL2 diabetes constitute one of the principal topics of interest in contemporary diabetes research. Because the regulated spatio-temporal positioning of motile immune cells is usually a precondition for the targeted destruction of specific parenchymal tissues, the pathogenesis of type 1 diabetes is usually both dependent on factors that control immune cell trafficking and potentially susceptible to therapeutic modalities that interfere with the bioactivity of such factors. With at least VULM 1457 46 individual members, the human chemokine superfamily constitutes perhaps the single largest group VULM 1457 of molecules involved in the recruitment of leukocytes to sites of inflammation (13), and multiple chemokines and chemokine receptors have emerged as pertinent contributors to the natural history of various autoimmune disorders, including type 1 diabetes; potential biomarkers; and possible drug targets (48). In fact, work conducted over the past 20 years has implicated more than one-half of all human and/or rodent chemokines in the pathogenesis of type 1 diabetes and/or its complications, although much of the work published to date on human type 1 diabetes and chemokines remains limited to genetic association studies and chemokine/receptor analyses in peripheral blood (923). In several mouse models, however, the expression of individual islet-associated chemokines has been used as a foundation for the development of pathogenesis and intervention studies that directly implicate chemokines, such as CCL2, CCL3, CCL5, CCL22, and CXCL10, in type 1 diabetes development (1423) and VULM 1457 demonstrate that this chemokine/receptor blockade of CCL3, CCR5, CCL22 or CXCL10 (1517,19,21), and Cxcl10 DNA vaccination (22) can ameliorate pathology and at least partially prevent the onset of type 1 diabetes. Although these studies support the VULM 1457 potential utility of targeting the chemokine system in type 1 diabetes models, the disparate nature of the chemokines involved and the lack of complete success in preventing type 1 diabetes by chemokine-specific monotherapies suggest the need to consider therapeutic interference with more than one relevant chemokine/receptor. This point is illustrated in an elegant study by Martin et al. (13), who exhibited the presence of multiple chemokine proteins (CCL1/3/4/21/22/24 and CXCL9/10) produced by islet-infiltrating cells, -cells, and/or endothelial cells in prediabetic nonobese diabetic (NOD) mice and showed that -cellspecific expression of the MHV68 protein M3, a decoy receptor that binds multiple chemokines, can in fact completely prevent spontaneous type 1 diabetes in the NOD model. Taken together, these findings emphasize the complex regulation of autoimmune responses by different chemokines as well as the possibilities and challenges associated with multiple therapeutic targets among members of the chemokine family. In the current study, we have combined a human islet culture system, animal models, and the immunohistology of human pancreata to develop an unbiased approach for the identification of those chemokines that are in fact expressed in the context of type 1 diabetes pathogenesis and thus may constitute suitable targets for the development of therapeutic strategies. == RESEARCH DESIGN AND METHODS == == Pancreatic tissue donors. == Pancreatic tissue sections were obtained through the Network for Pancreatic Organ Donors with Diabetes (nPOD) and included healthy control subjects (three donors VULM 1457 unfavorable for autoantibodies; case identification nos. 6112, 6115, and 6117) and type 1 diabetic donors at different disease stages (three donors with no evidence for other autoimmune disorders; case identification nos. 6036, 6052, and 6087). BMI for all those patients was in the range of 1726 kg/m2, and all other data are.