Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

Abstract

Antibody‐mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti‐donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti‐inflammatory therapy. Depletion or neutralization of anti‐pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG‐degrading enzymes do not deplete IgM. Despite the expression of human complement‐regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti‐C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell‐targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti‐inflammatory agents, anti‐IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti‐inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ‐source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD‐L1, HLA E, and/or HLA‐G.

Xenotransplantation literature update March 2023–November 2023

“…As previously noted, antibody‐mediated rejection (AMR) is currently the main immunological barrier to long‐term xenograft success. While AMR can be reversed in allografts, there is no reported successful AMR reversal in pig xenografts as reported a recent comprehensive review 27 . Strategies to prevent or reverse AMR in xenotransplantation are less established, and therapies include antibody depletion, complement inhibition, B cell and plasma cell targeting, and anti‐inflammatory agents.…”

“…Strategies to prevent or reverse AMR in xenotransplantation are less established, and therapies include antibody depletion, complement inhibition, B cell and plasma cell targeting, and anti‐inflammatory agents. Combining systemic complement inhibition with anti‐inflammatory agents may be the most effective approach, and further genetic engineering of source pigs may be necessary for a comprehensive solution 27 . Efforts to characterize human anti‐pig xenoimmune responses lead to the development of an animal model utilizing pig artery tissues transplanted into mice with human immune system 28 …”

Current challenges in xenotransplantation

“…Currently, there is no standard immunosuppressive regimen applied in preclinical pig-to-primate xenotransplantation studies. However, based on the best results achieved in recent NHP studies, a regimen based on an induction with antithymocyte globulin, rituximab, and C1 esterase inhibitor, and a maintenance therapy with an anti-CD154 monoclonal antibody (mAb), rapamycin, methylprednisolone and tocilizumab has been proposed as a possible regimen to prevent the onset of antibody-mediated rejection in preclinical studies [ 14 ▪ ].…”

“…Possible approaches to mitigate protracted inflammatory responses triggered by innate immune cells in xenografts could be the use of organs from genetically modified pigs expressing anti-inflammatory genes like human HO-1 [ 9 ▪▪ , 21 ] and A20 [ 22 ]. In this context also the use of anti-inflammatory agents such as tocilizumab, a monoclonal antibody against the human receptor for the proinflammatory interleukin (IL)-6, or etanercept, a tumor necrosis factor (TNF)-α inhibitor, appears to be associated with beneficial effects and has been suggested in the early post-transplant period as a means to counteract the inflammatory response, the induced T cell response and antibody production [ 10 ▪ , 14 ▪ ].…”

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

“…Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate (NHP) organ transplantation, even when the graft is from a pig with multiple genetic modifications 1,2 . The specific factors that initiate AMR are often uncertain, but may be associated with (1) inadequate gene editing in the pig, or (2) inadequate immunosuppressive therapy.…”