HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

Abstract

HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient’s HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient’s antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor.

Graft vasculopathy of vascularized composite allografts in humans: a literature review and retrospective study

“…Such modalities include variations in T AE B cell depletion, steroid-based and steroid-sparing maintenance regimens, switching from calcineurin-based inhibition to rapamycin and/or belatacept, and donor BMC infusion. DSA formation was detected in 3 of 5 VCA patients (#3, 8,9,12,13) who had undergone basiliximab or ATG induction followed by steroid-based maintenance immunosuppression but only in 1 of 5 (patients #4, 5, 6, 7, 10) who had undergone alemtuzumab induction and steroid-sparing maintenance protocols (albeit initially). Perhaps the earlier detection of GV in the latter group and subsequent introduction of additional maintenance steroids halted further progression.…”

Matching donor and recipient based on predicted indirectly recognizable human leucocyte antigen epitopes

“…Human leucocyte antigen (HLA) mismatches between donor and recipient may lead to alloreactive immune responses after clinical transplantation, thereby eliciting graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT) and graft failure after solid organ transplantation (Dunn et al, 2011;Rizzari, Suszynski, Gillingham, & Matas, 2011;Vu et al, 2011). Despite the development and use of immunosuppressive therapies over the past decades, alloreactive B-cell and T-cell responses towards mismatched HLA still cause GVHD and graft failure nowadays (Zachary & Leffell, 2016). Therefore, avoidance of these alloreactive B-cell and T-cell responses towards mismatched HLA will significantly improve the transplant outcome.…”

Concepts of Genomics in Kidney Transplantation

“…Unfortunately, waiting for an optimal match between donor and recipient results in a balance between the risk associated with increased wait time and the risk associated with increased mismatches. 2 …”