Proinflammatory Events and HLA Antibodies: Nothing to Sneeze At

In this issue of AJT, Locke et al. (1Locke JE Zachary AA Warren DS et al.Proinflammatory events are associated with significant increases in breadth and strength of HLA –specific antibody.Am J Transplant. 2009; Abstract Full Text Full Text PDF Scopus (101) Google Scholar) report that proinflammatory events, ranging from bacterial infections to myocardial infarctions, are associated with an increase in the breadth and strength of HLA antibodies among patients previously sensitized to HLA antigens. While suspected for years, descriptions of this relationship were all anecdotal. As the first report to assess the data scientifically, Locke et al. have presented reasonable evidence to conclude that the suspicions were true. The question now is what to do with this information. The authors advocate more frequent monitoring of highly sensitized patients, citing that such antibodies in transplant recipients are associated with higher rates of rejection and graft loss compared to unsensitized patients. However, these data were collected prior to the development of sensitive solid phase techniques and likely represent a failure to have detected donor specific antibodies (DSA) pretransplant. More recent data reveals that highly sensitized patients without DSA have graft survival essentially identical to unsensitized patients (2Bray RA Nolen JD Larsen C et al.Transplanting the highly sensitized patient: The Emory algorithm.Am J Transplant. 2006; 6: 2307-2315Crossref PubMed Scopus (176) Google Scholar). Nonetheless, the appearance (or reappearance) of DSA in a transplant recipient may be a reason for concern and an impetus to initiate aggressive therapy to prevent graft rejection (3Burns JM Cornell LD Perry DK et al.Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8: 2684-2694Crossref PubMed Scopus (180) Google Scholar). However, others report that DSA positive patients with stable renal function (4Bartel G Regele H Wahrmann M et al.Posttransplant HLA alloreactivity in stable kidney transplant recipients – Incidences and impact on long-term allograft outcomes.Am J Transplant. 2008; 8: 2652-2660Crossref PubMed Scopus (58) Google Scholar) and no episodes of antibody mediated rejection (5Lefaucheur C Suberbielle-Boissel C Hill GS et al.Clinical relevance of preformed HLA donor specific antibodies in kidney transplantation.Am J Transplant. 2008; 8: 324-331Crossref PubMed Scopus (183) Google Scholar), have excellent graft function/survival and caution not to regard DSA as problematic unless there is graft dysfunction. Currently, the patients most likely to be at risk for early posttransplant development of DSA are those patients who had DSA prior to transplant and underwent desensitization (3Burns JM Cornell LD Perry DK et al.Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8: 2684-2694Crossref PubMed Scopus (180) Google Scholar). Such patients are already being monitored closely since they are known to be at risk for adverse outcomes. Would they benefit from more frequent monitoring if they experience a proinflammatory event posttransplant? Perhaps, although it is unknown whether increase in antibody activity after a proinflammatory event are sustainable and/or clinically relevant. Locke et al. did not indicate whether the 23 patients transplanted across a positive crossmatch who experienced a proinflammatory event and had an increase in the breadth and strength of HLA antibodies had a worse outcome compared to 19 positive crossmatch patients without a documented inflammatory event. Other important groups of patients to consider are those who are unsensitized and those who, while sensitized, are transplanted without any history of DSA. Do these categories of patients need frequent monitoring for de novo DSA anytime they experience an infection or other proinflammatory event? As Locke et al. reported, the increased breadth of HLA activity following an inflammatory event was due to an expansion of antibodies within the same cross reactive group (CREG) as antibodies previously detected in the patient and not to the development of ‘new’ antibodies, As an example, consider two patients with well defined antibodies; one moderately sensitized (current PRA = 47%), the other, highly sensitized (current PRA = 87% PRA). The antibodies identified in the highly sensitized patient have been stable over a three- year period (certainly a time frame when a proinflammatory event is likely to have occurred) and never included specificities (private or CREG) against donor antigens. In contrast, antibodies in the moderately sensitized patient have waxed and waned during that same time frame and while none of the antibodies appeared to be donor directed, they were against the same CREG as one of the mismatched donor antigens. Do both patients require increased antibody monitoring after an inflammatory event? As Locke et al. note, >80% of renal transplant recipients develops an infection during their first posttransplant year. Importantly, the overall rate of antibody-mediated rejection in these patients is less than 5%. Unquestionably, Locke et al. raise an interesting and potentially important association between proinflammatory events and the subsequent expression of HLA antibodies. However, based on the sheer number of inflammatory events that can occur, the diversity of patients receiving transplants (sensitized, unsensitized and desensitized) and the unknown duration, stability and clinical significance of the antibodies that develop are major variables that should be considered. Prospective outcome studies are needed before routine monitoring for HLA antibodies postinflammation can be endorsed.

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