Abstract
Clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. Although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. Since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss. Fortunately, recent advances where consistent long-term survival (≥6 months) of adult porcine islet grafts was achieved in five independent, diabetic nonhuman primates (NHPs) enabled us to investigate on the late graft loss. Regardless of the conventional immune monitoring methods applied in the post-transplant period, the initiation of late graft loss could rarely be detected before the overt graft loss observed via uncontrolled blood glucose level. Thus, we retrospectively analyzed the gene expression profiles in 2 rhesus monkey recipients using peripheral blood RNA-sequencing (RNA-seq) data to find out the potential cause(s) of late graft loss. Bioinformatic analyses showed that highly relevant immunological pathways were activated in the animal which experienced late graft failure. Further connectivity analyses revealed that the activation of T cell signaling pathways was the most prominent, suggesting that T cell-mediated graft rejection could be the cause of the late-phase islet loss. Indeed, the porcine islets in the biopsied monkey liver samples were heavily infiltrated with CD3+ T cells. Furthermore, hypothesis test using a computational experiment reinforced our conclusion. Taken together, we suggest that bioinformatics analyses with peripheral blood RNA-seq could unveil the cause of insidious late islet graft loss.
Highlights
Intravenous glucose tolerance test (IVGTT) had shown that the porcine islet graft loss in R080 was in progress between DPT120 and 180 (Fig. 1a~d, processed from published data15)
Since recent report showed gene expression perturbation in peripheral blood could reflect graft site event[17,18], we performed RNA sequencing with the archives of whole blood samples taken at four different time points from graft-losing R080 vs. graft-stable R051 (Fig. 1e) to explore the cause of chronic islet loss happened in R080
We and others have found that the porcine islet grafts were lost in the transplant recipient monkeys within 6~30 months after transplantation in pig-to-nonhuman primates (NHPs) islet xenotransplantation[32]
Summary
Over half of the patients transplanted with human islets returned to the insulin-dependent, diabetic state within 5 years[3,4] The causes for this late islet graft loss are still controversial. We reported consistent long-term (≥6 months) porcine islet graft survivals in five independent monkeys[15]. This unique opportunity allowed us to examine how the porcine islets are lost in the late phase of islet xenotransplantation. We selected two monkeys with the same immunosuppressive regimen to analyze the cause of late graft loss in islet xenotransplantation: one (R051) had stable graft function for the entire follow-up periods and the other (R080) lost graft function around 160 days post-transplantation (DPT). Further in silico analyses focused on the interactions of graft loss period-related activated pathways (GLPAPs) proposed that lymphocytes- or platelet-mediated rejection might have been the cause of late graft loss
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