Mechanism and Treatment of Antibody-Mediated Rejection Reference: Stegall M.D, Gloor JM. Deciphering antibody-mediated rejection: new insights into mechanisms and treatment. Curr Opin Organ Transplant. 2010;15:8–10.

Antibody-mediated rejection (AMR) after positive cross-match kidney transplantation is a difficult situation for clinicians and so is for the patient. However, now with better visibility in AMR pathogenesis across varied clinical settings and newer and better effective therapy options are emerging.

Donor-Specific Alloantibody and Rejectionsin Crossmatch Kidney Transplantation Antibody-mediated rejection in positive crossmatch kidney transplantation cases has been attributed by a steep increase in the donor-specific alloantibody (DSA) during the initial few weeks of post-transplantation. The rise in DSA production could be due to the plasma cells, which are already existing or arising from recipient memory B cells.

Through several sensitive crossmatch assays that are available today, it has been established that renal transplant subjects have DSA levels around a broad-spectrum and not all DSA lead to hyperacute rejections. Donor antibody gives rise to diverse pathologic changes. Hence, AMR could be observed in association with cellular rejection in an earlier unsensitized kidney recipient or AMR may occur only due to antibody like the ones observed soon post-transplantation in patients subjected to desensitization protocols for a positive cross-match. Reasons for the development of AMR during the desensitization phase are unknown. According to Burns et al. recipients with high levels of DSA in the first month following transplantation almost invariably had AMR, while patients with low DSA levels had no rejection.

Mechanisms of Antibody Production during Antibody-Mediated Rejection Cellular mechanisms behind AMR are unknown; however, recent studies indicate at the alloantibody produced in sensitized patients as a major cause. Pre-existing plasma cells or the conversion of allospecific memory B cells to plasma cells could be responsible for the antibody production. Studies supporting the memory B cells activity during AMR are not available. Irrespective of this various groups have created AMR treatment protocols, built on their presumed effect on plasma or B cells.

Current Treatment Modality for AMR Intravenous Immunoglobulin and Plasmapheresis Currently, high-dose intravenous immunoglobulin (IVIGs) and plasmapheresis (PP) are the chosen treatment protocols followed for desensitization and AMR. Lefaucheur et al. studied the efficacy of both the treatment options in recipients in the initial 3 months of post-transplant. The patients were treated for AMR with high-dose IVIg only or with combination of IVIg/ anti-CD20/plasma-pheresis antibody, rituximab. At 36 months, the graft survival in the patient group receiving IVIg only and the IVIg/anti-CD20/plasmapheresis antibody, rituximab was 50% and 91.7%, respectively. The study findings also reveal that in graft loss patients the level of DSA post-treatment was higher. This and other studies do not give a clear picture on the effects of rituximab on memory B cells or the efficacy of treating AMR with only plasmapheresis.

Current Treatment Modality for AMR Proteasome Inhibition for Treating AMR: A Novel Approach One way of treating AMR would be by controlling the DSA production. Bortezomib, a proteasome inhibitor, approved by the FDA for multiple myeloma can be used for AMR treatment. Bortezomib through apoptosis of normal plasma cells can reduce production of alloantibody recipients under sensitization protocol. The role of proteasome inhibition for achieving low levels of DSA has also been supported by Perry et al. In another study by Everly et al. it was observed that patients who underwent proteasome inhibition had lower levels of DSA but they also developed transplant glomerulopathy. The absence of controls limits the opportunity of studying the true efficacy of proteasome inhibition.

Current Treatment Modality for AMR Use of Eculizumab Terminal Complement Inhibition C4d+ staining of the peritubular capillaries has demonstrated the role of early complement activation in AMR. Eculizumab, FDA-approved humanized monoclonal antibody, which has high C5 affinity inhibits the terminal complement activation. Locke et al. have studied the use of eculizumab in successfully treating a severe AMR patient. Terminal complement can also prevent AMR development.

Transplant Glomerulopathy Development in AMR Transplant glomerulopathy, is a key chronic damage seen in AMR, with above 40% of AMR patients at the risk of developing the chronic histologic lesion. Trivedi et al. studied the efficacy of bortezomib in decreasing antibody levels through the denovo production of anti-HLA antibodies. The authors advocate that the use of bortezomib may prevent chronic antibody-mediated damage.

Conclusion Further investigation and follow-up are required to evaluate if these novel therapies are effective enough in enhancing AMR clinical outcomes. In addition, the immunologic mechanisms behind the increased DSA levels and the role of memory B cells in comparison to pre-existing plasma cells should be studied. Based on the occurrence of Banff criteria of AMR across various seemingly dissimilar clinical settings, it is apt to investigate if there are different ‘types’ of AMR existing. Also, it remains to be established whether chronic antibody mediated injury will follow successful treatment of AMR.