Cum hoc sed non propter hoc
Journal
American Journal of Transplantation
Journal Volume
17
Journal Issue
7
Pages
1960-1961
Date Issued
2017
Author(s)
Abstract
To the Editor: We are thankful to Carter and colleagues for their interest in our recently published article (1Carter V Howell WM Shaw J Donor specific antibodies – The devil is in the detail.Am J Transplant. 2017; (https://doi.org/10.1111/ajt.14253.)Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Analyzing the cases of 42 pancreas islet recipients from the GRAGIL network, we confirmed that pancreas islet grafting is an HLA-sensitizing event. In our cohort, one-third of islet graft recipients developed alloantibodies directed against mismatched HLA molecules expressed by the graft. The diversity of the repertoire and the titer of donor-specific antibodies (DSAs) were highly variable, and maintenance immunosuppression appeared to protect against DSA generation (2Pouliquen E Baltzinger P Lemle A et al.Anti-donor HLA antibody response after pancreatic islet grafting: Characteristics, risk factors, and impact on graft function.Am J Transplant. 2017; 17: 462-473Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Interestingly, and in marked contrast with solid organ transplantation (where antibody-mediated rejection is widely considered the main cause of transplant failure (3Sellares J de Freitas DG Mengel M et al.Understanding the causes of kidney transplant failure: The dominant role of antibody-mediated rejection and nonadherence.Am J Transplant. 2012; 12: 388-399Abstract Full Text Full Text PDF PubMed Scopus (1077) Google Scholar)), the appearance of DSAs did not seem to accelerate the rate of islet graft attrition in our cohort (2Pouliquen E Baltzinger P Lemle A et al.Anti-donor HLA antibody response after pancreatic islet grafting: Characteristics, risk factors, and impact on graft function.Am J Transplant. 2017; 17: 462-473Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). While our conclusion has since been confirmed in an independent single-center study (4Chaigne B Geneugelijk K Bdat B et al.Immunogenicity of anti-HLA antibodies in pancreas and islet transplantation.Cell Transplant. 2016; 25: 2041-2050Crossref PubMed Scopus (26) Google Scholar), it is in striking disagreement with a previous report, which found an absolute association between de novo DSA onset and graft loss in five islet recipients (5Brooks AM Carter V Liew A et al.De novo donor-specific HLA antibodies are associated with rapid loss of graft function following islet transplantation in type 1 diabetes.Am J Transplant. 2015; 15: 3239-3246Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). In their correspondence, Carter and colleagues propose that the results of the two studies might have been more closely aligned if we had performed an earlier posttransplantation DSA assessment. Indeed, in our study, the first detection of DSAs was performed 12 months after the last grafting procedure, while all five recipients of Newcastle’s group developed alloantibodies within 4 weeks postgrafting and had a failed graft at 12 months (5Brooks AM Carter V Liew A et al.De novo donor-specific HLA antibodies are associated with rapid loss of graft function following islet transplantation in type 1 diabetes.Am J Transplant. 2015; 15: 3239-3246Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). If this hypothesis was true, one would expect in our cohort a higher incidence of DSAs in recipients with failed versus functional islet grafts at 12 months: it is clearly not the case (DSA-positive recipients with failed vs. functional islet graft: 0 of 7 vs. 3 of 35, p = 0.42). Another critical difference between the two studies is the method used to assess pancreatic islet function. In the work by Brooks et al, this evaluation relied on a C peptide stimulation test. However, previous studies have reported (i) a low correlation of C peptide levels and graft function due to confounding effects of blood glucose and renal function and (ii) that exogenous insulin requirements were the metabolic parameters that correlate best with graft function. Therefore, the beta score used in our study that incorporates insulin requirements, fasting blood glucose, C peptide, and hemoglobin A1c certainly represents a better tool to monitor islet graft function. One could debate indefinitely about the subtle methodological differences that may account for the discrepancies between the results of the clinical studies. The truth is that clinical approach, which can at best establish correlation (and not causality), will never reach a definitive conclusion on whether DSAs have a detrimental impact on islet graft survival. Indeed, the generation of DSA requires that allogeneic CD4+ T cells help B cells to differentiate into antibody-producing plasma cells. Hence, DSA appearance could be a “marker but not maker” of islet rejection. In other words, DSA appearance could reflect an ongoing alloimmune T cell response involving not only CD4+ T cells (leading to DSA generation) but also CD8+ cytotoxic T cells, which may be responsible for the destruction of grafted islets. Therefore, it is clear that only experimental approaches, which allow uncoupling of the cellular and humoral arms of the alloimmune system, will determine whether DSAs truly affect graft survival. Our group has recently initiated a research program inspired from the seminal work of Colvin and colleagues (6Russell PS Chase CM Winn HJ Colvin RB Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity.J Immunol. 1994; 152: 5135-5141Crossref PubMed Google Scholar), in which immunocompromised mice lacking T and B cells are used as recipients of an allogeneic graft and passively infused with DSAs. These efforts will hopefully shed light on the intriguing question of islet-graft resistance to DSAs. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
SDGs
Type
journal article