Pretransplant Immune Parameters Associate With Islet Allograft Outcome

Extensive and informative immunological assessments of islet transplant recipients have been limited due, in part, to the smaller numbers of patients transplanted compared with solid organ trials. Limitations related to blood volume and the logistical challenges of collecting multiple posttransplant samples for drug levels as well as clinical and metabolic parameters also pose challenges. Several variables affect islet allograft outcome, including alloand autoimmune responses to transplanted islets, -cell mass and islet quality, efficacy of the immunosuppressive regimen and its effect on islet function, as well as glycemic control. In fact, much debate has centered on whether or not islet attrition is due to immune-mediated loss, death of overworked cells caused by insufficient mass, and/or diabetogenic effect of various immune intervention agents. In addition, many of these parameters may have differing effects based on the transplanted mass, with marginal mass transplants being more susceptible to immunemediated or stress-induced loss. Recently, several studies have demonstrated immunological alterations in islet allograft patients. Posttransplant changes in lymphocytes and lymphocyte subsets were reported to be variable depending on the immune suppression used but have not yet been associated with graft status or specific clinical outcomes (1–4). Higher posttransplant cytotoxic T-cell precursor frequency against donor antigens was associated with poorer outcome at 6 months in recipients treated with sirolimus-based maintenance therapy but not tacrolimus–mycophenolate mofetil (5). In one study, cytokine production in allogeneic mixed lymphocyte reactions (MLRs) was skewed toward a Th2 profile in recipients who achieved insulin independence, but no differences were noted between groups prior to transplant (6). Hyporesponsive posttransplant MLRs have been observed in islet recipients treated with steroid-free immune suppression (3) and in islet/stem cell recipients (2), with increases above baseline occurring subsequent to graft rejection. All of these findings are associated with eventual graft outcome, as opposed to demonstration of predictive changes in the posttransplant period, and provide indications to the immunological alterations that have occurred in successfully transplanted recipients. Elevation of cytotoxic lymphocyte gene expression has been shown to predict impending islet allograft rejection in nonhuman primates (7) and clinical islet transplant recipients (2,3,8). Alloantibodies are generally not observed until a patient has already lost significant islet function and immune suppression is being tapered or has been discontinued (3,9), and autoantibody status has not been proven to impact islet allograft outcome (2,3,10). In the absence of a clinical assay that is associated with rejection, such as creatinine for renal and amylase for pancreatic allografts, the lack of a validated marker of islet rejection remains a challenge to be overcome and limits the ability to interfere at an early stage of graft loss. In this issue of Diabetes, Hilbrands et al. (4) demonstrate that higher baseline total and B lymphocyte cell counts, as well as T-cell autoreactivity to islet antigens, are associated with poorer islet transplant outcome. The analyses of immune and graft outcome parameters included 30 nonuremic, C-peptide–negative type 1 diabetic patients who received an intraportal islet cell graft under the cover of anti-thymocyte globulin induction and maintenance with tacrolimus and mycophenolate mofetil. Absolute leukocyte, lymphocyte, and lymphocyte subset (T-, B-, and natural killer cell) counts, autoantibodies, and T-cell autoreactivity were compared with achievement of insulin independence, plasma C-peptide, and glycemic variability at 6 months posttransplant. Fifteen patients were insulin independent at 6 months and were compared with those who were not. Observed correlations from univariate analysis were further examined in a multivariate model. At baseline, patients who would ultimately become insulin independent had significantly lower total lymphocyte, as well as CD19 Band CD3 T-cell counts, with a lower count of CD3/8 T-cells contributing to the difference in CD3 cells. There was no association between baseline autoantibody positivity and graft outcome. However, Tcell autoreactivity against IA-2 and/or GAD was lower at baseline in the group that became insulin independent; this effect was specific for recipients of suboptimal -cell mass (4,11). The authors conclude that prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first posttransplant year. As previously mentioned, the logistics of posttransplant sample collection are challenging, and the blood volume required for many assays necessitates that relatively few samples are collected over time, with quarterly monitoring being fairly standard. This background, together with the constantly changing immunosuppressive landscape, makes it difficult to convincingly demonstrate the utility/ From the Department of Surgery and Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida. Corresponding author: Camillo Ricordi, [email protected]. DOI: 10.2337/db09-1147 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 2267. COMMENTARY