Kidney transplantation is the most common solid organ transplant and the best current therapy for end-stage kidney failure. However, with standard immunosuppression, most transplants develop chronic dysfunction or fail, much of which is due to chronic immune injury. Tregs are a subset of T cells involved in limiting immune activation and preventing autoimmune disease. These cells offer the potential to provide tolerance or to allow reduction in immunosuppression in kidney transplants. The importance of Tregs in kidney transplantation has been shown in a number of seminal mouse and animal studies, including those with T cell receptors (TCRs) transgenic Tregs (TCR-Tregs) or Chimeric Antigen Receptor (CAR) Tregs (CAR-Tregs) showing that specificity increases the potency of Treg function. Here we outline the animal and human studies and clinical trials directed at using Tregs in kidney transplantation and other tolerance settings and the various modifications to enhance allo-specific Treg function in vivo and in vitro.

BackgroundThe cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy.MethodsWe administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice.ResultsBAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33–treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33–stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)–depleted splenocytes. Wild-type mice infused with IL-33–treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution.ConclusionsIL-33–expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.