Desensitization in HLA-incompatible kidney transplant recipients: current strategies and emerging perspectives

Abstract

Despite development of kidney paired donation programs and prioritization in kidney allocation schemes, transplantation rates are still low and waiting times remain prolonged for highly sensitized kidney transplant recipients with broad human leukocyte antigen antibody reactivity. Desensitization confers an invaluable option improving access to kidney transplantation for sensitized patients who could not benefit from kidney paired donation programs and kidney allocation schemes. Conventional desensitization strategies use intravenous immunoglobulin combined with either plasmapheresis or monoclonal anti-CD20 antibodies. Imlifidase, IL-6 targeting agents, plasma cell-directed therapies, complement inhibitors, chimeric antigen receptor T-cell therapies, and B cell-activating factor inhibitors are emerging new options in the hope of enhancing and sustaining the efficacy of desensitization to improve allograft longevity. In this review, we discuss the rationale and outcome of desensitization with various strategies alone or in combination. Our aim is also to provide some insight for decision when pursuing desensitization might be successful or futile in sensitized patients.

Keywords: CAR T-cell therapies; desensitization; kidney transplantation; plasma cell-directed therapies; plasmapheresis.

Figure 1:

Desensitization strategies and post-transplant monitoring in patients undergoing HLA-incompatible KT. w, weekly; m, monthly; UTI, urinary tract infections; BKV, BK virus; CMV, cytomegalovirus; EBV, Ebstein–Barr virus; PVB19, parvovirus B19; dd-cfDNA, donor-derived cell-free DNA.

Figure 2:

Crucial steps toward institution of B-cell alloimmunity and action sites of multiple desensitization strategies interfering immune effector mechanisms. APCs present HLA antigens to naive T cells. Activated T and B cells migrate to GC and the former differentiate into Tfh cells. These cells stimulate proliferation and differentiation of GC B cells, which lead to generation of memory B cells or antibody-producing short- (plasmablasts) and long-lived plasma cells. Plasmablasts secrete IL-6, augmenting formation of more germinal centers. Binding of antibodies to the allograft endothelium may invoke NK cell, macrophage and neutrophil activation through FcγR and induce complement activation via the classical pathway. Co-stimulation blockers, agents blocking survival factors and monoclonal antibodies acting through interleukin-6/IL-6 receptors may disrupt GC formation, hinder B-cell activation and differentiation, hamper the formation or durability of plasma cells. CD38 monoclonal antibodies interfere with antibody-producing plasma cells and NK cells while proteosome inhibitors deplete plasma cells. Complement inhibitors either disrupt the C1 complex or block the terminal component C5 and the formation of the MAC. DSAs can be addressed directly either by cleaving IgG with imlifidase or antagonizing the FcRn that accelerates the catabolism of IgG. *The immunomodulatory activity of IVIG is provided by multiple inhibitory actions on B and T cells, and complement cascade activation, antibody formation, and recycling. APC, antigen presenting cell; CP, classical pathway; FcγR, Fc gamma receptor; FcRn, Fc neonatal receptor; LLPC, long-lived plasma cells; MAC, membrane attack complex.

Figure 3:

Desensitization in HLA-incompatible KT: current aspects, future trends, and research directions.