Reacción a "Joint heart-kidney transplant tested in macaques to avoid rejection and immunosuppressants"

The study conducted by Tonsho et al. is of high scientific quality. It is published in Science Translational Medicine, a highly prestigious journal in the biomedical field, which is ranked in the first decile, tertile and quartile in the “Medicine, Research and Experimental” category, ranking 2 out of 189 journals, with a percentile of 98.9%. The study used a preclinical model with non-human primates, which are more representative experimental models of human physiology compared to rodents and pigs, as they had previously done. They have compared different transplantation strategies (isolated heart transplantation vs. combined heart-kidney transplantation) under well-controlled conditions. Multiple analyses, such as RNA sequencing, detailed histology and immunological studies, were used, which adds robustness to the conclusions.

The study is very interesting and follows the same line of research of this group, who had already performed similar experiments in mice and also in pigs. In this work they have scaled it up to primates and delved into the underlying mechanism of immunotolerance. It goes without saying that the rejection of our immune system to an external organ or tissue is much more potent than to any infection. Also that previous studies on tolerance induction had already revealed an organ-specific hierarchy: the kidney and liver exhibit an enhanced form of immune privilege and are prone to tolerance, whereas the heart and lungs are largely resistant to tolerance.

In this study they have observed that generating transient mixed hematopoietic chimerism through the combination of non-myeloablative conditioning and donor bone marrow transplantation (DBMT) and accompanied by kidney transplantation (with immune privilege) can establish systemic tolerance allowing long-term survival of co-transplanted organs such as the heart, which were originally refractory to tolerance induction. They also suggest that allograft acceptance is not due to host immunological ignorance or incompetence, but to an active process initiated and/or mediated by the donor kidney, leading to robust systemic tolerance and, consequently, long-term cardiac allograft survival. Therefore, in this work they have also demonstrated the phenomenon of “Kidney-Induced Cardiac Allograft Tolerance” (KICAT) in a preclinical non-human primate model.

The study is based on previous evidence on the induction of immunologic tolerance by donor bone marrow transplantation, which has been effective in kidney transplantation, but not in cardiac transplantation. The main novelty is the demonstration that cotransplantation of kidney and heart from the same donor can induce long-term tolerance in primates without the need for immunosuppression. A potential mechanism has been identified based on lymphoid structures rich in regulatory T cells (Foxp3+) in transplanted kidneys, which appear to contribute to heart tolerance.

The implications are significant, since this strategy could be applied in patients with heart and end-stage renal failure who require a combined transplant. If translated to clinical practice, it could reduce dependence on immunosuppressive drugs and their adverse effects, improving the quality of life of patients and prolonging graft survival.

The study has several limitations to consider. It should be said that the authors acknowledge that, although the study is promising, the exact mechanisms behind tolerance are not yet fully understood and further research is needed for its application in humans. The following limitations should be noted:

• Animal model: although primates are valuable preclinical models, extrapolation to human patients requires further clinical studies.
• Relatively small sample size: could influence the generalizability of the results.
• Follow-up time: Despite promising long-term results in primates, longer follow-up is needed to assess the durability of tolerance in humans. However, it is worth noting that some of the recipients were monitored for more than 5 years and with periodic biopsies to rule out both acute and chronic rejection.
• Individual immunological factors: Genetic variability in humans could affect the reproducibility of these results, especially in relation to histocompatibility between donor and recipient.
• Postoperative complications: Some animals developed disorders such as post-transplant lymphoproliferative disorders (PTLD) and persistent anemia, indicating that there are still clinical risks to be evaluated in humans.

Finally, I would like to highlight that two pathologists (Ivy A. Rosales and Robert B. Colvin), affiliated with the Department of Pathology, Massachusetts General Hospital, Boston, MA, USA, a renowned institution for its expertise in transplantation and pathology, participated in the study, which lends credibility to the histopathological evaluation of the grafts in the study.