Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus

Abstract

Tacrolimus and Sirolimus are commonly used maintenance immunesuppressants in kidney transplantation. Since their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of Tacrolimus to Sirolimus conversion on frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late Sirolimus conversion and 12 on Tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12 and 24-months post-randomization with T cell subpopulations analyzed by flow cytometry and T cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24-months post-randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4+25+++Foxp3+ regulatory T cells. While Tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post-transplant, Sirolimus conversion increased indirect alloreactive T cell frequencies compared to Tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in Sirolimus-converted patients. Thus, chronic immune alterations are induced after Sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

“…We hypothesized that, while naïve and effector T cells would be profoundly inhibited by AZD2014 in transplant recipients, Treg and Tfh subsets that are known to be less dependent on mTOR-mediated metabolism, 11,36,37 might be relatively spared. We analyzed splenic CD4, CD8, Treg and Tfh cells 7 and 21 days posttransplant.…”

Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act

“…This is highlighted in studies where removal of CNI in liver or kidney transplant patients increased Treg frequencies in PBL . Similarly, conversion from CNI to rapamycin or to mycophenolate mofetil (MMF) increased the numbers and fraction of Tregs in PBL . Thus, CNI are potent inhibitors of effector immune responses, but are equally detrimental to Treg homeostasis.…”

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans

“…Of these, CD25 16,17 , CD69 17,18 , CD71 16,17 , CD134 19 , CD137 19,20 , CD154 19 and LFA1α 21 have been used in transplantation to identify alloreactive T cells. The glycoproteins CD44 21–23 or CD45 isoforms 24 , markers of antigen experience, are also used to distinguish naive from effector and memory cells. Markers of cell-cycle entry such as Ki67 can also identify recently activated T cells 23 .…”

“…Such an analysis of circulating T cells revealed clonal T cell deletion as 1 of the mechanisms of clinical tolerance in recipients of combined donor bone marrow and renal allografts 27 . Allospecific regulatory T cells (Tregs) also express markers of activation and proliferation in response to their cognate alloantigen in an MLR, and can be identified by staining with Foxp3-specific antibodies 17,24,28 .…”