Current Desensitization Strategies in Heart Transplantation

Abstract

Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.

Management of the sensitized heart transplant candidate

“…Ig to highly sensitized HT candidates, in one study, circulating antibody levels decreased from 70.5% to 30% resulting in negative prospective flow crossmatch and successful transplant in all patients with comparable 5-year survival to nonsensitized patients [41]. However, although rituximab is a standard component of desensitization in HT candidates [15,42,43], its role in desensitization is limited to case reports and case series [44,45]. Furthermore, another concern with rituximab was evident when used as induction in nonsensitized HT recipients in the CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) trial.…”

From bench to bedside: reversing established antibody responses and desensitization

“…Although left ventricular support devices (LVADs) may be an alternative for some heart transplant candidates, not all patients qualify and complications limit the duration of support, so transplantation remains the gold-standard. Moreover, LVADs further drive sensitization serving as a unique risk factor to this population [65 ▪ ]. Immunologically, LVAD-related sensitization is often characterized by a robust HLA antibody response early after implant that decays over time [66].…”

Induction Therapy in the Current Immunosuppressive Therapy

“…Highly sensitized patients, and those with positive cross-match may also have been considered as the candidate for the induction therapy in the past, however, since evidence for desensitization therapy is being established, truly high risk patients for hyperacute antibody-mediated rejection with high intensity of donor-specific should be considered more specific desensitization rather than introduction immunosuppressive therapy. And induction therapy may be generally used in combination with desensitization therapy, not induction therapy alone [3,5]. Patients with pre-existing renal dysfunction may still be the best indication of induction therapy in the current clinical situation [17][18][19][20].…”

“…Immunosuppressive regimens for organ transplantation can be generally characterized as induction, maintenance, or rescue therapies [2]. Recently, desensitization therapy has also been considered for recipients who are highly sensitized to Human leukocyte antigen (HLA) or have donor specific HLA antibodies [3]. Induction immunosuppressive therapy is a powerful and prophylactic therapy that is used perioperatively to prevent episodes of acute rejection, which is expected to improve the clinical prognosis or make their managements easier in high-risk HTx recipients.…”