Intermediate-Term Graft Loss After Renal Transplantation is Associated With Both Donor-Specific Antibody and Acute Rejection

Abstract

Development of dDSA was associated with an increased incidence of graft loss, yet the detrimental effect of dDSA was limited in the intermediate term to recipients with AR.

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“…Although our comparisons of dnDSA among the 2 immunosuppressive regimens are novel, beyond these novel findings the study should be viewed as observational and exploratory in terms of both pathogenicity of dnDSA over time and type of immunosuppressant agent or regimen and outcomes (endpoints such as GFR, proteinuria, and graft survival would require longer follow-up and/or greater number of participants). Our rate of dnDSA prevalence is high compared with a number of reports 1,25 but is consistent with others, 24 perhaps due to the low threshold applied for defining dnDSA as MFI > 500 and accounting for each dnDSA occurring at any time within each time point (1,6, and 12 mo) rather than at a specified time point (thereby accounting for dnDSA that may wax and wane). Importantly, to ensure with the greatest confidence that dnDSA incidences were indeed de novo, we explicitly defined dnDSA as those DSA episodes that were not only undetectable at the time of transplant but also that occurred at any point before transplant from the time of being placed on a wait list (or from September 2009 if wait listing occurred before this date).…”

“…Although we did not specifically identify the chronology of acute rejection relative to dnDSA formation, we and others have previously demonstrated that dnDSA may precede or follow clinical episodes of acute rejection and the combination is associated with graft loss. 1,5,24 Although dnDSA to class II antigens (especially DSA to DQ antigens) is often reported to predominate, we did not find a strong predisposition to class II versus class I, with a mixed class I and II picture as the most common finding.…”

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

“…Studies involving pediatric and adult kidney transplant only and kidney-pancreas transplant recipients have also shown that the development of de novo donor-specific anti-HLA-DQ antibody was associated with a #10-fold greater risk of developing early and late AMR, which was often associated with development of transplant glomerulopathy and early graft loss (14)(15)(16). In our study, we have highlighted the importance of class 2 mismatches and the risk of acute rejection.…”

Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment

“…Two considerations make it seem unlikely that the involvement of sHLA in allograft outcome is merely a bystander effect. First, there is the ability of the sHLA to bind to receptors on CD8+ T cells [171,[156][157][158][159], with such interaction capable of inducing apoptosis of CD8+ cells and arresting of cytolytic capability [141,156,157]. Second, there is the recent report of a monospecific monoclonal anti-HLA-E antibody able to induce proliferation and blastogenesis of CD8+ cells in vitro [93].…”

“…The molecular mechanism underlying interaction between sHLA-I and CTL is illustrated in the works of Puppo, et al [156,157], who clearly documented that sHLA-I antigens purified from serum interact through their α3 domain with the α chain of CD8 molecules and that this interaction triggers apoptosis in PHA-activated CD8 + CD95 + T cells. These observations lend support to the contention that-after dissociation of β 2 m-the β2m-free HC of HLA-I do indeed interact with CD8+ CTL through the α3 domain.…”