The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

Abstract

Central to the humoral theory of transplantation is production of antibodies by the recipient against mismatched HLA antigens in the donor organ. Not all mismatches result in antibody production, however, and not all antibodies are pathogenic. Serologic HLA matching has been the standard for solid organ allocation algorithms in current use. Antibodies do not recognize whole HLA molecules but rather polymorphic residues on the surface, called epitopes, which may be shared by multiple serologic HLA antigens. Data are accumulating that epitope analysis may be a better way to determine organ compatibility as well as the potential immunogenicity of given HLA mismatches. Determination of the pathogenicity of alloantibodies is evolving. Potential features include antibody strength (as assessed by antibody titer or, more commonly and inappropriately, mean fluorescence intensity) and ability to fix complement (in vitro by C1q or C3d assay or by IgG subclass analysis). Technical issues with the use of solid phase assays are also of prime importance, such as denaturation of HLA antigens and manufacturing and laboratory variability. Questions and controversies remain, and here we review new relevant data.

Transplant glomerulopathy

“…63,64 Perhaps, more important than donor-specific antibody directed against donor serologic antigens may be antibodies reacting with donor-specific epitopes not present in the recipient. 65,66 Such epitopes may be shared among HLA antigens and hence not be recognized simply by considering donor serologic antigens. For example, in a study of 17 allograft nephrectomy specimens,~20% of HLA antibodies were directed against donor-specific alleles, whereas 80% were directed against donor specific epitopes.…”

“…Whether epitope matching would reduce development of de novo donor-specific antibody and subsequently transplant glomerulopathy remains to be proven. 66 If donor-specific antibodies are detected, either preformed or de novo, close clinical surveillance as well as serial titration and protocol biopsy may identify the earliest stages and potentially prevent progression. There is some evidence that early, for example, at cg1a, appropriate treatment may forestall progression.…”

A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival

“…HLA-specific B-cell ELISPOT assays could provide additional insights on this (22,23). Another suggested mechanism is that nDSA can contribute to graft injury by epitope sharing between the nDSA specificities and donor-specific antigens (24,25). The suggested reduced graft survival in patients with nDSA against class I and II, might rather be the result of the high number of retransplants and subsequent broad allosensitization as reflected by a median peak PRA of 36 (IQR 11-53).…”

Cardiac Non-Human Leukocyte Antigen Identification: Techniques and Troubles

“…Human leukocyte antigen (HLA) mismatch is the primary barrier to allograft transplantation, although recent studies ( 22 – 24 ) have highlighted the role of non-HLAs in initiating or modulating rejection responses. Current clinical recommendations rely heavily on pre- and postoperative assessment of anti-HLA antibodies for prediction and monitoring of rejection episodes ( 25 ). Significant improvements have been made in HLA-matching by the use of modern solid phase flow techniques such as single antigen bead (SAB) technology for virtual cross-match with HLA epitope matching (Figure 1 ) ( 25 ).…”

“…Current clinical recommendations rely heavily on pre- and postoperative assessment of anti-HLA antibodies for prediction and monitoring of rejection episodes ( 25 ). Significant improvements have been made in HLA-matching by the use of modern solid phase flow techniques such as single antigen bead (SAB) technology for virtual cross-match with HLA epitope matching (Figure 1 ) ( 25 ). However, HLA responses alone are insufficient to account for all deleterious immune responses observed in transplant recipients.…”