Noninvasive diagnosis of recurrent autoimmune type 1 diabetes after islet cell transplantation

Abstract

Islet cell transplantation is curative therapy for patients with complicated autoimmune type 1 diabetes (T1D). We report the diagnostic potential of circulating transplant islet-specific exosomes to noninvasively distinguish pancreatic β cell injury secondary to recurrent autoimmunity vs immunologic rejection. A T1D patient with hypoglycemic unawareness underwent islet transplantation and maintained normoglycemia until posttransplant day 1098 before requiring exogenous insulin. Plasma analysis showed decreased donor islet exosome quantities on day 1001, before hyperglycemia onset. This drop in islet exosome quantity signified islet injury, but did not distinguish injury type. However, analysis of purified transplant islet exosome cargoes showed decrease in insulin-containing exosomes, but not glucagon-containing exosomes, indicating selective destruction of transplanted β cells secondary to recurrent T1D autoimmunity. Furthermore, donor islet exosome cargo analysis showed time-specific increase in islet autoantigen, glutamic acid decarboxylase 65 (GAD65), implicated in T1D autoimmunity. Timematched analysis of plasma transplant islet exosomes in 3 control subjects undergoing islet cell transplantation failed to show changes in islet exosome quantities or intraexosomal cargo expression of insulin, glucagon, and GAD65. This is the first report of noninvasive diagnosis of recurrent autoimmunity after islet cell transplantation, suggesting that transplant tissue exosome platform may serve as a biomarker in islet transplant diagnostics.

Application of exosomes as liquid biopsy in clinical diagnosis

“…In islet transplantation, Vallabhajosyula et al 125 demonstrated that proteomic and RNA signatures, quantity and other signal changes in donor HLA exosomes could indicate early injury/loss of islet mass; therefore, transplant islet exosomes could be a reliable biomarker for monitoring patients undergoing islet transplantation over long-term follow-up. Recently, Korutla et al 133 reported a relevant case confirming that circulating transplant islet-specific exosomes could be a potential biomarker for distinguishing between pancreatic β cell damage secondary to autoimmune relapse or immune rejection in islet-transplanted patients diagnosed with autoimmune type 1 diabetes.…”

Advances in β-cell replacement therapy for the treatment of type 1 diabetes

“…30,31 Rejection can be difficult to distinguish from recurrent autoimmunity, although monitoring of donor-specific alloantibodies and islet-specific autoantibodies might be helpful. 32 T-cell auto reactivity and alloreactivity assays are not readily available in the clinical setting. 33…”

Exosomes and Their Noncoding RNA Cargo Are Emerging as New Modulators for Diabetes Mellitus

“…For instance, adipocyte-derived stem cell exosomes exert ameliorative effects on T1DM by multiple pathways, including modulating the immune cell response [54], attenuating podocyte damage [55], and promoting proangiogenic properties [56]. Nonetheless, exosomes can be developed as an effective tool to improve islet transplant by modulating the immune response or as a biomarker of recurrent autoimmunity for islet transplant diagnosis [57,58].…”