Abstract
Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.
Highlights
Kidney transplantation is the best treatment for kidney failure, in terms of length and quality of life and costeffectiveness,[1,2] but a significant number of patients keep their transplants for less than 10 years,[3] returning to dialysis as the transplant fails
We recently reported the findings of a long-term observational study in patients with a transplant biopsy diagnosis of chronic antibody-mediated rejection (AMR) (CAMR),[7] describing the activity of antidonor T cells recognizing donor antigen via the indirect pathway.[8]
human leukocyte antigen (HLA) Abs are a marker of B-cell activation, which is a T-cell–dependent process involving cognate interactions between B and T cells, so it follows that DSAs are markers of “indirect” CD4þ T-cell sensitization to donor antigens
Summary
Kidney transplantation is the best treatment for kidney failure, in terms of length and quality of life and costeffectiveness,[1,2] but a significant number of patients keep their transplants for less than 10 years,[3] returning to dialysis as the transplant fails. We recently reported the findings of a long-term observational study in patients with a transplant biopsy diagnosis of chronic AMR (CAMR),[7] describing the activity of antidonor T cells recognizing donor antigen via the indirect pathway.[8]. Two-thirds of nonreactive samples had evidence of suppression of antidonor IFN-g production by CD19þ B lymphocytes or CD25þ T cells, challenging the prevalent hypothesis that patients with chronic rejection have lost the ability to regulate antidonor cellular immunity.[9]. We expand our findings from the same cohort by describing the dynamic changes in ELISPOT patterns in individual patients and report an association with changes in estimated GFR (eGFR), testing the hypothesis that progression of renal dysfunction is influenced by the activity of Kidney International (2017) 91, 477–492 clinical investigation. Further investigation of the importance of cellular immune responses in AMR may promote a deeper understanding of how to treat chronic rejection
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