Importantly, the generation of tolerance (reduced immune response against a graft in the absence of immunosuppressive treatment) is one of the great challenges in the field of transplantation, as it would eliminate the immunosuppression that organ recipients currently require for life with a significant burden of side effects and would prolong graft survival time.  

The study is an advance on previous results published by the same group, which had already succeeded in inducing tolerance to kidney grafts in humans and non-human primates by combined transplantation with bone marrow from the same donor. In this study, performed in non-human primates, the authors observe that when bone marrow and kidney from the same donor are transplanted, the kidney seems to collaborate with the tolerogenic effect of haematopoietic tissue, which allows the acceptance of third organs, such as the heart (which does not have this effect on its own) and even on fourth grafts, such as the skin, which they also evaluate. The authors do not demonstrate the cause, which is a limitation of the study, although they correlate their findings with the appearance of certain lymphoid tissue in the kidney, in which the presence of foxP3-positive T-regulatory lymphocytes stands out.  

The work is methodologically sound, although another limitation is that the results are not the same in all cases in the study group, and some even develop rejection of the heart graft after some time.    

In short, the study represents an advance towards achieving immunological tolerance in the field of organ transplantation, although it is difficult to assess whether these results would be reproducible in humans.

There are two fundamental limiting factors for the development of transplantation. On the one hand, the supply/demand disproportion, which is trying to be improved either by organisational measures or by the use of genetically modified animals, so far with little success. On the other hand, rejection remains the sword of Damocles for transplant recipients, and the immunosuppressive drugs available, apart from not being able to prevent it 100%, have a multitude of side effects, especially in the long term. Hence, one of the main avenues of current research is to achieve a state of ‘immunotolerance’: to ensure that the transplant recipient tolerates the organ as if it were his or her own and therefore does not need immunosuppressive drugs, or only in low doses, thus avoiding their harmful effects and achieving indefinite survival of the transplant.

This article is along these lines. One of the most studied procedures to achieve immunotolerance is to combine organ transplantation with a bone marrow or other form of haematopoietic progenitor transplant from the same donor preceded by preparative treatment. Promising results have been obtained with various abdominal organs, but not in cardiac transplantation, which raises many questions. What the authors have done using great apes as experimental animals is to transplant either a heart, or a heart associated with a kidney and bone marrow transplant from the same donor. Immunotolerance was induced only when the kidney was associated with the transplanted heart, a situation in which the animals did not experience rejection. 

In discussing the mechanisms by which this phenomenon could occur, which the authors call KICAT (kidney-induced cardiac allograft tolerance), they rule out a number of possibilities such as the erythropoietin produced by the kidney or a greater or lesser genetic similarity between donors and recipients, and conclude that it is due to the presence in the kidney of lymphatic structures rich in a type of T-regulatory cells that would not be present in the heart. Similar structures may explain why combined transplants involving the liver as one of the organs generate fewer rejections than those involving other organs in isolation.

The article represents an undoubtedly interesting experimental contribution to a better understanding of how to deal with immunotolerance in the clinic. Combined heart-kidney transplantation represents 5% of all heart transplants in North America (in Spain it is less than 1%) and therefore the authors propose the need for common protocols that allow for a deeper understanding of this phenomenon and improve results.

This work advances the search for tolerogenic mechanisms to avoid the use of long-term immunosuppression in solid organ transplantation.  

It is a unique model and difficult to transfer for now to humans, since joint kidney-heart transplants have not demonstrated the findings obtained here with primates, probably because in humans a level of immunosuppression is used that does not allow for the possible cellular chimerism that the authors claim could be responsible for tolerance.

The paper does not find a clear mechanism that induces it, although it suggests a possible increase of regulatory T cells in lymphoid organs in the kidney itself. There is no change in circulating lymphocytes in the blood and no gene expression to suggest such a mechanism. They do show an absence of antibodies and effector T cells alloreactive against the transplanted organ.  

This is interesting work in the search for mechanisms to induce immunological tolerance to avoid the use of long-term immunosuppression.

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.