Research published in the American Journal of Transplantation has shown that using the cancer drug Bortezimib in combination with costimulation blockade can prolong allograft survival in sensitized non-human primates that received a kidney transplant, a finding that may have important to the treatment of patients at greater risk of antibody-mediated rejection.
What is antibody-mediated rejection, and how is it important to transplantation?
Antibody-mediated rejection (AMR), caused by antibody produced against the donated organ (“alloantibody”), is an important source of graft loss in kidney transplant recipients. Although alloantibody is usually produced after transplantation, some individuals express graft-specific antibody prior to the procedure (“sensitization”) due to previous organ transplants, transfusions, or pregnancy.
This is highly problematic, since sensitized individuals are ineligible for organ transplantation from living donors, even if living donors are otherwise available. Improving methods for preventing the production of alloantibody and desensitizing individuals with existing alloantibody will support long-term graft survival, increase the number of living-donor organ transplants, and improve transplant outcomes.
Alloantibody is produced mainly by immune cells known as “plasma cells” which result from the activation and expansion of graft-specific B cells. This graft-specific antibody targets and binds to features of the transplanted kidney, supporting the assault of immune cells on the organ which eventually results in severe tissue damage and graft failure.
What is Bortezimib?
Previous research suggests that the anti-cancer drug Bortezomib, which targets and kills cells with high levels of metabolic activity, could also be useful for desensitizing transplant recipients and preventing graft rejection by eliminating alloantibody-producing plasma cells.
However, this desensitization therapy was not found to be as effective as hoped, and was hypothesized to be limited by the expansion of graft-specific B cells in the lymph nodes in the weeks following transplantation (“homeostatic germinal center response”).
Dr. Christopher Burghuber, Dr. Stuart Knechtle, and their team from Duke and Emory University investigated whether the simultaneous dual inactivation of plasma cells and the upstream homeostatic germinal center response could promote desensitization and combat AMR.
To this end, they treated non-human primates that received a kidney transplant with both Bortezomib, to eliminate plasma cells, and costimulation blockade involving the monoclonal antibodies anti-CD28 (Belatacept) and anti-CD40, to inactivate B cells involved in the homeostatic germinal center response.
This combination therapy was demonstrated to be more effective at desensitization and preventing graft rejection than Bortezomib alone, reducing levels of circulating alloantibody and the proliferation of immune cells involved in graft rejection. The researchers found that this treatment combination encouraged desensitization, lowered the incidence of graft loss, and extended graft survival.
These findings have important implications. Since more effective methods for desensitization could expand the number of living-donor organ transplantations, this combination therapy could increase organ availability for individuals desperately in need of a transplant.
Importantly, however, there were significant drawbacks: the therapy was associated with “significant infectious complications and drug toxicity.” Only time will tell whether it is truly beneficial and could reach the clinic.
Future studies will assess the mechanisms underlying the efficacy of this combination therapy and potentially unsafe treatment-related health complications in greater detail.
Burghuber CK, Manook M, Ezekian B, et al. (2019) Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. American Journal of Transplantation, 19(3):724-736.
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