Intestinal Transplantation and Donor-Specific Antibodies: Another Brick in the Wall.

Abstract

Potential conflict of interest: Nothing to report. In the last 20 years, intestinal transplantation (IT) has become an important part of the treatment of intestinal failure. However, patients treated with home parenteral nutrition in specialized centers have far better longterm survival outcomes than those treated with IT. The intestine remains one of the most difficult organs to transplant because of poor longterm graft survival, mostly due to its immunological properties: The innate and adaptative immune systems exchange continuously with the bowel content (food or microbiota) in the middle of 80% of our body’s immune‐reactive cells. Learning from nephrologists, intestinal transplant teams 10 years ago began to consider the role of anti‐HLA donor‐specific antibodies (DSAs) in rejection. Accumulated data support their detrimental role in the short‐term and longterm prognosis of IT.1 The results may be controversial, however, because the numbers are often small and the patients vary in age, indication for IT, type of graft, immunosuppressive protocols, and nonimmunological complications. For example, the number of patients developing de novo DSAs ranges from 18% in adults in Pittsburgh2 to 80% in our pediatric experience.6 All DSAs are probably not equal, preformed, de novo, class I or II, or low or high level. In 2017, the Intestinal Transplant Registry reported on 3452 patients (including 1843 children) who received transplants since 1985.7 The scientific data are therefore based on totals of individual centers that network in the small world of IT rather than on large randomized studies. In a new study5 in which the numbers are once again small (5 children with preformed DSA, 7 de novo DSA, 16% of the cohort), preformed DSAs were not deleterious and were at least treatable. Patients with a positive crossmatch received a protocol of desensitization (plasmapheresis and immunoglobulins), which was effective in 3 patients (1 nonevaluable). The untreated patient had a negative crossmatch and noncomplement‐binding DSAs and did not reject the transplant. De novo DSAs were correlated with graft loss if they were complement‐binding, which was the case in 5 of 7 patients. This study is only the second to explore the impact of this harmful property of DSAs after IT.6 As in previous studies in which DSAs were usually class II or I and II, a single patient had isolated class I DSAs, which were not complement‐binding or deleterious. The transplanted liver seemed to be protective against the formation of de novo DSAs but not for graft survival because the significance of the “liver inclusive” factor together with “underlying disease,” “induction,” and “maintenance immunosuppression,” was lost in the multivariate analysis. This is probably due to small numbers and confounding factors such as the general status of these children and the other complications after combined liver‐intestine transplantation. The protective role of the liver is therefore not defined in this study. In previous studies, longterm graft survival was improved with a liver‐inclusive graft, but these patients received a transplant when humoral rejection was not yet recognized. Yet will the “liver effect” persist now that early antibody‐mediated rejection may be controlled? The diagnosis of humoral rejection relies not only on DSAs but on clinical and pathological findings. In our experience, the symptoms must be mild to achieve reversal. In this study, biopsies were performed because of diarrhea, and among the 11 patients with rejection (4 with DSAs), 9 lost their graft and 1 died (Supporting Table 2). This is an argument to continue performing protocol biopsies to detect early reversible signs. The pathologist should look for capillaritis or microthrombosis, which are signs of vascular involvement. We have shown that positive complement component 4d (C4d) staining is correlated with the complement‐fixing capacity of DSAs6 and that rejection is often both humoral and cellular. Although pathology details are not provided, the treatment was mostly aimed at cellular rejection (steroids, thymoglobulin, or alemtuzumab), which could explain the high rate of graft loss. In summary, this study provides further arguments for monitoring DSAs before and after IT and exploring their function (binding of complement) more than their subtype and fluorescence index. C4d staining could be considered a surrogate marker. Although desensitizing a patient with noncomplement‐fixing DSAs with a negative crossmatch would still be considered, collection of data would be helpful in view of the protocol cost and aggressiveness. The DSAs should be correlated with the pathological findings, with special interest to the vessels, and a specific treatment for humoral rejection should be proposed. Data on DSAs and pathology in longterm surviving patients should be collected to determine their role in late graft survival.