In recognition of the transient character of sole antibody removal, therapy protocols for AMR or pretransplant desensitization mostly include B-cell–directed agents, usually anti-CD20 antibodies with a B-cell depleting effect. Rituximab has been the first clinically available anti-CD20 antibody and has been used in the management of autoimmune disorders and hematologic diseases since 1997. The available literature in solid organ transplant almost uniformly used rituximab for B-cell depletion. Newer agents include the humanized antibody ofatumumab, with greater efficiency toward cells with lower CD20 expression,100 obinutuzumab, which shows less lipid raft relocalization of CD20 resulting in less complement dependent but more direct cytotoxic B-cell depleting effects,101 and ublituximab, which provides enhanced antibody-dependent cellular cytotoxicity through glycoengineering.102 While extensive comparison studies are underway, mostly in various settings of the therapy of hematological neoplastic disorders, none of these agents has thus far been evaluated in a structured study for AMR in solid organ transplant and the available published data are limited to case reports. Whether potential benefits on rituximab resistance or low CD20-expressing lymphoma cells are relevant in the setting of depletion of healthy B cells in the setting of AMR is unclear but could be target of future studies.
When differentiating into plasmablasts and PCs, CD20 expression is lost on the B-cell surface. Accordingly, PCs and LLPCs will not be depleted by rituximab therapy, and following isolated rituximab therapy, a measurable reduction of allospecific antibodies is expected with at least 3 months delay after natural demise of the short-lived PCs with no new supply following. Persistence of some degree of new antibody production has been observed in both animal models27 and human trials and is likely associated with continuous low-level antibody production by LLPC. In human therapy trials, the picture is heterogenous because anti-CD20 therapy is almost always combined with intravenous immunoglobulin therapy (IVIG), often with antibody removal therapies and sometimes with PC-directed therapies.
It becomes obvious that rituximab therapy as a sole intervention will rarely be a suitable strategy in the clinical setting due to delayed and limited effectiveness. The addition of high-dose (2 g/kg body weight every 4 wk) IVIG does not only provide protection from infections to the recipient but also provides immune modulation via negative feedback, alteration of the cytokine milieu, and blockade of the Fc receptors of many immune cells. Whether the IVIG also has a regulatory effect on LLPC remains unclear, however, appears plausible. Interestingly, single time pretransplant therapy with rituximab was found to result in long-term persistent reduction of antibodies directed toward the AB blood group antigens in the setting of ABO-incompatible solid organ transplant in adults103 and older children.104 This is in keeping with the hypothesis that the mostly TI activation of B cells toward these polysaccharide antigens105 is predominantly provided by the splenic MZ B cells and IgM-expressing MBC106 and possibly no bone marrow–resident LLPC are toward AB antigens.
Anti-CD19 antibodies would provide a broader therapeutic application because CD19 expression persists throughout B-cell activation and in PCs. Treatment with anti-CD19 has been found to inhibit the production of allospecific IgG in animal trials107; however, clinical application thus far has not gone beyond phase II trials, mostly in hematologic–oncologic settings. More recent trials have included CD19 into chimeric antigen receptors and may result in promising therapeutic options for the future.108
Antithymocyte globulins (ATGs) are generated by injection of human thymic tissue and cell lysates into animals. Consequently, they are polyclonally directed against a variety of human lymphocyte surfaces including common leucocyte antigens (CD52), HLA epitopes, and other surface markers shared between many lymphocytes including B cells such as CD5 and CD27. Accordingly, some degree of B-cell depletion is expected in the context of ATG therapy either as induction agent or for acute cellular rejection. However, the effect seems much less pronounced on B cells than T cells, and lymphocyte subtype analysis post-ATG therapy commonly shows B cells as the predominantly remaining cell type. At present, there is no evidence of a significant antibody-reducing effect of ATG; however, a clinical benefit for the graft may arise in the individual situation from limiting the downstream effects of antibodies as well as the T-cell support of activated B cells.
Proteasome inhibitors were initially developed for therapy of neoplastic proliferation of PC-derived tumor cells (multiple myeloma) but found to also induce apoptosis in regular PCs, resulting in reduced anti-HLA antibody production.109 Clinical efficacy against AMR was shown in small studies as part of combination therapies with antibody removal, IVIG, and B-cell depletion.110 However, subsequent trials including a recent placebo-controlled study111 suggest that bortezomib therapy lacks long-term efficacy on HLA antibodies and is not effective to prevent graft deterioration in AMR late after transplant.112 This lack of long-term efficacy is observed despite mechanistic studies showing that proteasome inhibitors (bortezomib, carfilzomib, and new agents under development) in vitro not only reduce immunoglobulin production and survival of peripheral blood PCs but also induce apoptosis in B cells including MBC. The discrepancy between in vitro effects and limited efficiency in vivo may be due to microenvironmental factors in secondary lymphatic organs and especially a lack of effect on LLPC resident in the bone marrow; however, there are no available experimental data to confirm this hypothesis, and given the lack of access to theses, LLPC in a human setting is unlikely to be generated. In mice, bortezomib showed a limited effect on antiplatelet antibody-producing LLPC in vitro, but these cells had been isolated from their bone marrow environment and stimulated in isolated cultures.113
Teasing out individual effects of antibody-directed therapies in the clinical setting is extremely difficult because the majority of trials concomitantly use multiple modalities. There is good rationale for this approach; however, some considerations have to go into planning of a desensitization or AMR treatment protocol:
Memory reactivation resulting in newly formed PCs and persistence of antibody production by bone marrow–resident, immune-privileged LLPCs reflect synergistic and redundant systems providing highly effective antibody-mediated immune response to previously encountered antigens. Accordingly, no single target therapeutic strategy is likely to fully succeed in providing complete resolution of antibody-mediated effects on a transplanted organ. Modalities that are effective in vitro are often limited by microenvironment factors in vivo. Therapeutic combination approaches targeting B-cell memory, PCs, antibody concentration, and downstream effects are currently the most promising, albeit not perfect, approach to prevent antibody-mediated harm from the graft.
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