Cotransplanting kidney, heart prevents heart transplant rejection

Scientists have validated a unique protocol that can extend the survival of heart transplants in nonhuman primates without the need for immune suppression. Their studies build on previous preclinical work showing that cotransplanting hearts along with kidneys and bone marrow can prevent heart transplant rejection, addressing a longstanding obstacle in the field.

Organ rejection remains a major concern for patients who have received organ transplants, and is a leading cause of transplant failure. Currently, most patients take immune-suppressing drugs to avoid rejection, but these medications need to be taken for life and have many side effects. Therefore, scientists are researching strategies that can coax the immune system into tolerating foreign organs and tissues without the need for immune suppression.

Previously, scientists showed that two procedures called nonmyeloablative conditioning followed by donor bone marrow transplantation (DBMT) could establish tolerance of kidney transplants in nonhuman primates, extending the organs’ lifespans. However, replicating this success with heart transplants has been more difficult. Makoto Tonsho from Massachusetts General Hospital, Boston and the first author of the study and colleagues tested whether transplanting kidneys along with hearts from the same donor could induce long-term survival of the transplanted hearts.

They developed a protocol where they performed donor bone marrow transplantation a week before organ cotransplantation, and compared cynomolgus monkeys that received either a heart transplant alone or both a heart and kidney transplant from the same mismatched donor. The transplanted hearts survived for much longer without immune suppression in the dual transplantees compared with animals that received hearts alone. The results were published in the journal Science Translational Medicine.

Further research tied this tolerance to lymphoid structures in the kidneys that were rich in regulatory T cells, which are known to have immune-calming properties. “Tolerant heart allografts showed gene expression profiles very similar to immunosuppressed heart allografts, suggesting an active process of ongoing immune quiescence,” says the Editor’s summary. As a step towards clinical translation, the authors also adapted their protocol for deceased donor organ transplantation, with donor bone marrow transplantation using cryopreserved donor bone marrow several months after heart/kidney transplant, to support translation to human patients.

“RNA sequencing analysis revealed that gene expression in hearts from tolerant recipients closely resembled that in hearts from chronically immunosuppressed recipients but differed markedly from rejecting allografts and naïve hearts. A version of this protocol may be able to induce tolerance in patients with end-stage heart and kidney failure who require combined heart and kidney transplantation,” the authors write.