What is the clinical relevance of deviant serum calcium and phosphate levels after pig-to-primate kidney xenotransplantation?

Experience from human renal allotransplantation informs us that disturbances in serum calcium and phosphate levels are relatively common. Post-transplant hypercalcemia is associated with an increased risk of recipient mortality, but not of graft loss or nephropathy, and post-transplant hyperphosphatemia with an increased risk of both recipient mortality and death-censored graft failure, but neither post-transplant hypocalcemia nor hypophosphatemia is associated with adverse outcome. Studies after pig-to-nonhuman primate kidney xenotransplantation have demonstrated consistent supranormal serum calcium and subnormal serum phosphate levels. If these trends in serum electrolyte levels were to occur following pig-to-human kidney xenotransplantation, the data from allotransplant studies would indicate an increased risk of recipient mortality (associated with hypercalcemia) but not of graft loss or nephropathy, and no adverse outcome from hypophosphatemia. Furthermore, some nonhuman primates are now surviving in a healthy state for longer than a year after life-supporting pig kidney transplantation, suggesting that chronic hypercalcemia and/or hypophosphatemia are not detrimental to long-term survival, and should not prevent clinical trials of pig kidney transplantation from being undertaken.

Immunological selection and monitoring of patients undergoing pig kidney transplantation.

Pig kidney xenotransplantation has the potential to alleviate the current shortage of deceased and living human organs and provide patients with end-stage renal disease with a greater opportunity for long-term survival and a better quality of life. In recent decades, advances in the genetic engineering of pigs and in immunosuppressive therapy have permitted the resolution of many historical obstacles to the success of pig kidney transplantation in nonhuman primates. Pig kidney xenotransplantation may soon be translated to the clinic. Given the potential risks of kidney xenotransplantation, particularly of immunologic rejection of the graft, potential patients must be carefully screened for inclusion in the initial clinical trials and immunologically monitored diligently post-transplantation. We provide an overview of the immunological methods we believe should be used to (i) screen potential patients for the first clinical trials to exclude those with a higher risk of rejection, and (ii) monitor patients with a pig kidney graft to determine their immunological response to the graft.

Uterus transplantation: the importance of uterine natural killer cells.

PURPOSE OF REVIEW: Murine studies have established that uterine natural killer (uNK) cells are critical regulators of normal placentation and fetal development in mammals. However, the biology of uNK cells in humans remains poorly understood. This ignorance represents a costly knowledge gap, as disordered placentation is thought to underpin a variety of pregnancy complications that impact maternal and neonatal health. In the context of uterus transplantation (UTx), uNK cells are anticipated to play a critical role within the allograft. Here, we review the current understanding of uNK cells in pregnancy biology and explore how this critically important cell population may contribute to pregnancy and graft outcomes in uterus transplant recipients. RECENT FINDINGS: Recent studies have characterized differences in NK cell populations between anatomic compartments in humans. In the endometrium, at least five phenotypically and functionally distinct subpopulations of uNK cells have been identified, with research into mechanisms regulating their differentiation and function currently underway. SUMMARY: Further elucidating uNK cell biology has the potential to influence the outcomes of pregnancy and UTx and benefit human health. UTx is a unique opportunity to study uNK cell biology and may shed light on mechanisms by which immunological tolerance is established at the maternal-fetal interface.

Hierarchical assembly and disassembly of a transcriptionally active RAG locus in CD4+CD8+ thymocytes.

Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ thymocytes. Rag1 and Rag2 gene expression in CD4+CD8+ thymocytes depends on Rag1 and Rag2 promoter activation by a distant antisilencer element (ASE). We identify GATA3 and E2A as critical regulators of the ASE, and Runx1 and E2A as critical regulators of the Rag1 promoter. We reveal hierarchical assembly of a transcriptionally active chromatin hub containing the ASE and RAG promoters, with Rag2 recruitment and expression dependent on assembly of a functional ASE-Rag1 framework. Finally, we show that signal-dependent down-regulation of RAG gene expression in CD4+CD8+ thymocytes depends on Ikaros and occurs with disassembly of the RAG locus chromatin hub. Our results provide important new insights into the molecular mechanisms that orchestrate RAG gene expression in developing T cells.