Abstract
Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment option for patients with Type I diabetes mellitus and end-stage kidney disease, but acute and chronic rejection remain obstacles to long-term allograft function. This study aimed to determine the role of immune responses to mismatched donor human leukocyte antigen (HLA) and tissue-restricted self-antigens (kidney and pancreas) in allograft rejection after SKP Tx.
Sera were collected from 39 SKP Tx recipients. Preexisting and post-transplant de novo antibodies specific for kidney-associated self-antigens (KSAgs) (i.e., collagen-IV, fibronectin) and pancreas-associated self-antigens (PSAgs) (i.e., insulin, islet cell, glutamic acid decarboxylase, pancreas-associated protein-1) were measured by ELISA. The sample was considered positive if values exceeded mean+2 standard deviations of healthy normal subjects samples. Donor-specific antibodies to HLA class I and II were determined using single antigen beads using Luminex assay.
Acute rejection was confirmed on biopsy in 23/39 patients (59%). Of these, 6/23 (26.1%) had kidney and pancreas rejection, 8/23 (34.8%) had kidney-alone rejection and 9/23 (39.1%) had pancreas-alone rejection. De novo development of antibodies to KSAgs and PSAgs was significantly higher in combined kidney-pancreas rejection patients compared with stable SKP Tx patients (p<0.05) and normal healthy subjects (p<0.05). SKP Tx recipients with kidney-alone rejection had significantly increased antibodies against KSAgs compared to stable SKP Tx recipients (<0.05) and normal healthy subjects (<0.05), but showed no increase in antibodies against PSAgs. Similarly, SKP Tx recipients with pancreas-alone rejection had significant increase in antibodies against PSAgs compared to stable SKP Tx recipients (<0.05) and normal healthy subjects (<0.05), but showed no increase in antibody development against KSAgs.
Development of antibodies to KSAgs and PSAgs is associated with combined kidney-pancreas rejection after SKP Tx. Kidney-alone rejection showed increased antibodies to KSAgs, and pancreas-alone rejection showed increased antibodies to PSAgs. This suggests that immune responses to tissue-specific antigens play a critical role in allograft rejection.