HLA Class I Sensitization in Islet Transplant Recipients: Report from the Collaborative Islet Transplant Registry

Abstract

Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and post-transplant human leukocyte antigen (HLA) class I sensitization rates in islet alone transplantation. Data came from 303 recipients transplanted with islet alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly post-transplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pre-transplant PRA was not predictive of islet graft failure. However, development of PRA ≥20% post-transplant was associated with 3.6 fold (p=.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions.

Long-Term Immunosuppression After Solitary Islet Transplantation Is Associated With Preserved C-Peptide Secretion for More Than a Decade

“…It has been shown previously (20,21) that withdrawal of immunosuppression, including the potent T cell inhibitor tacrolimus, within 3 years of a failing islet transplant increases anti-donor HLA antibody formation (22). HLA matching may play a role in preservation of functional islets, demonstrated by two cases (13,15) with encouraging outcomes of 10- and 13-year insulin independence.…”

The current challenges for pancreas transplantation for diabetes mellitus

“…However, the differing magnitudes of the procedures have meant that patients and clinicians prefer the less invasive islet transplantation, even though it requires more donor pancreases to produce a successful transplant and insulin independence is not certain (albeit may not be required) [8]. One of the unintended consequences of repeated islet transplants is the development of antibodies to human leukocyte antigens (HLA-antibodies) [9][10][11], which may limit access to future transplants of either islets, whole pancreas, or kidney. The latter is particularly relevant since the immunosuppression commonly used for islet (and pancreas) transplantation is nephrotoxic, and may hasten renal failure in patients with early nephropathy.…”

Autologous and Allogenous Antibodies in Lung and Islet Cell Transplantation

“…Multiple factors contribute to loss of islet grafts, including poor islet quality, posttransplant inflammation, immunosuppressive drug-induced toxicity, recurrent autoimmunity, β-cell exhaustion, and alloimmune responses (88). Primary causes of islet allograft rejection are thought to be incidences of β-cell directed autoimmunity in combination with the alloimmune response to multiple mismatched HLA antigens that significantly impact long-term islet cell function.…”

“…Rejection due to alloimmunity after islet transplantation is mainly due to the Abs against donor-specific HLA class I and II molecules (89, 90). Moreover, the requirement of multiple islet infusions to achieve insulin independence exposes transplant recipients to an unusually high number of HLA mismatches, resulting in elevated risk for a broader spectrum of donor-specific HLA Abs (88). Our group researched a possible role for HLA Abs in the rejection of islet allografts (91).…”

“…Unlike any other type of organ transplantation, allogeneic islet recipients could be exposed to a total of 9–25 HLA class I and II antigen mismatches. This extraordinarily high number of mismatches was likely due to the multiple HLA-mismatched pancreas donors used for islet isolation, and also possibly the result of increased risk of patients receiving any future transplants (88). A significant increase in the level of HLA Abs was seen, even when patients adhered to an immunosuppression regimen.…”