The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation

Abstract

SummaryAntibodies recognizing denatured human leucocyte antigen (HLA) can co-react with epitopes on intact HLA or recognize cryptic epitopes which are normally unaccessible to HLA antibodies. Their specificity cannot be distinguished by single antigen beads (SAB) alone, as they carry a mixture of intact and denatured HLA. In this study, we selected pretransplant sera containing donor-specific HLA class I antibodies (DSA) according to regular SAB analysis from 156 kidney transplant recipients. These sera were analysed using a SAB preparation (iBeads) which is largely devoid of denatured HLA class I, and SAB coated with denatured HLA class I antigens. A total of 241 class I DSA were found by regular SAB analysis, of which 152 (63%) were also found by iBeads, whereas 28 (11%) were caused by reactivity with denatured DNA. Patients with DSA defined either by regular SAB or iBeads showed a significantly lower graft survival rate (P = 0·007) compared to those without HLA class I DSA, whereas reactivity to exclusively denatured HLA was not associated with decreased graft survival. In addition, DSA defined by reactivity to class I SAB or class I iBeads occurred more frequently in female patients and in patients with historic HLA sensitization, whereas reactivity to denatured HLA class I was not associated with any of these parameters. Our data suggest that pretransplant donor-specific antibodies against denatured HLA are clinically irrelevant in patients already sensitized against intact HLA.

Impact of IgG3 Subclass and C1q-Fixing Donor-Specific HLA Alloantibodies on Rejection and Survival in Liver Transplantation

“…In order to facilitate the most accurate comparisons between the models, stepwise regression analysis was originally used but all variables from any model that were significant were ultimately forced into the final models to ensure exact similarity. (3) HLA antibodies detected using Luminexbased assays can react with denatured HLA antigens (32,(43)(44)(45)(46). Previous studies in renal and heart transplantation demonstrated that these antibodies are not clinically significant.…”

“…This cutoff was utilized because of prior data (18,21,22). Separate testing for denatured class I HLA antigens was not performed (32). The outcomes of patients based on pre-transplant (21) and de novo (22) standard DSA testing have been previously published.…”

Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation

“…The literature to date suggests that anti-dHLAs are irrelevant since they are unable to recognize the donor HLA target on the cell surface and therefore have no influence on graft function or survival [14,[21][22][23][24][25]. Consequently, in graft allocation programs, it seems unreasonable to consider the HLA antigens targeted by such antibodies as unacceptable mismatches.…”

Lung intragraft donor-specific antibodies as a risk factor for graft loss

“…[11][12][13][14][15][16] However, detection of serum DSA with SAFB has technical limitations, falsenegative and false-positive results being respectively caused by complement interference [17][18][19] and by anti-HLA antibodies of ill-defined pathogenic role recognizing denatured class I HLA molecules. [20][21][22][23][24][25] The presence of DSA is not synonymous with lung allograft injury. 26 The lack of direct association may be due to the inability of the DSA to bind to the graft because of the absence of expression of cognate HLA molecules, or because of insufficient binding strength between a low affinity DSA and its target.…”