Elucidating the role of trained immunity in kidney transplant patients

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SUMMARY – PROJECT 1 Historically, organ transplant immunologists have focused on the adaptive immune system, as organ rejection is mediated primarily by T cells. However, accumulating evidence indicates a distinct role for innate immune cells in the complex graft-reactive immune response. This P01’s investigators propose to modulate innate immune responses by targeting trained immunity, a long-term increase in the functional responsiveness of innate immune cells, which is maintained by epigenetic modifications and can be considered de facto innate immune memory. The members of Project 1 recently demonstrated in a mouse model of heart allograft transplantation that graft rejection can be prevented by therapeutically regulating trained immunity. Suppressing trained immunity yielded a tolerogenic milieu characterized by an accumulation of regulatory macrophages and regulatory T cells in the allograft. This change in the allograft microenvironment resulted in long-term graft survival without requiring immunosuppressive therapy. These results are corroborated by preliminary data in kidney transplant patients, showing that trained immunity is associated with 10-year graft survival. Based on these preclinical and clinical preliminary data, Project 1’s overall hypothesis is that trained immunity promotes graft rejection in kidney transplant patients. In Aim 1, we will study which circulating factors (e.g., danger-associated molecular patterns and proinflammatory cytokines) are produced as a result of ischemia-reperfusion injury during transplantation and how these impact graft survival by inducing trained immunity. Durable trained immunity requires epigenetic changes in bone marrow myeloid progenitors. In Aim 2, we will investigate how changes in the bone marrow influence the production and behavior of circulating monocytes and relate this to clinical outcomes, including graft survival. To accomplish these Aims, we have assembled a multidisciplinary team of investigators led by Project Lead Dr. Mulder, who will coordinate Project 1 and supervise a team of experienced co-Is: Dr. Duivenvoorden is a transplant nephrologist and will be responsible for the studies on kidney transplant patients, Drs. Mhlanga and Netea will be responsible for all RNA- and ATAC-sequencing in close collaboration with Core C. Project 1 will yield critical insights into the relation between trained immunity and graft survival in kidney transplant patients. These insights will open new diagnostic and therapeutic avenues for advancing patient care.