Pretreatment of Rapamycin Before Allogenic Corneal Transplant Promotes Graft Survival Through Increasing CD4+CD25+Foxp3+ Regulatory T Cells

Abstract

Key words: Rapamycin, Regulatory T cells, Corneal transplantCorneal disease, one of the leading causes of blindness in China, 1 requires a corneal transplant to restore visual function in most cases. 2 Although immune privilege of corneal allografts endows a high success rate of corneal transplant than other solid-organ transplants, immunologic rejection remains a major cause of graft failure after corneal transplant. 3,4 Regulatory CD4 + CD25 + Foxp3 + T cells (Treg), an important regulator in maintaining immune homeostasis, play a crucial role in autoimmune diseases and tumors, and protect individuals from graft rejection. 5 However, Treg cells are present in low numbers under normal conditions, reported to be 5% to 10% of CD4 + T cells in mice and human blood, and have an anergic phenotype. 6 Therefore, enhancement of activated Treg cells may protect individuals from autoimmune diseases and graft rejection, just as previous studies have revealed. [7][8][9][10] Rapamycin, a novel macrolide immunosuppressive drug, has been reported to prevent clinical allograft rejections including corneal allografts. 11 Moreover, rapamycin allows expansion of CD4 + CD25 + Foxp3 + Treg in vitro and in vivo, 12-14 and CD4 + CD25 + Foxp3 + Treg converted by rapamycin has more-potent regulatory abilities. 15 It has been shown that adoptive transfer of CD4 + CD25 + Foxp3 + Treg expanded by rapamycin in vitro is capable of artIClE

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

“…After skin allograft transplantation, imDCs carrying donor antigens trigger antigen-specific immune tolerance and promote the survival of allogeneic skin grafts [25]. Rapa has recently been confirmed as an immunosuppressant for antirejection due to its suppressive role in T cell activation [14]. In this study, imDCs pretreated with Rapa attenuated lymphocyte proliferation and enhanced cell apoptosis, compared with the imDC-treated group, despite comparable expression of cell surface MHC class II, CD11c and CD86.…”

“…Further analysis suggested a similar inhibitor effect on CD4 + cell proliferation stimulated with anti-CD3/CD28 antibodies. It is widely accepted that inducing the expansion of Tregs by imDCs is a common strategy for the induction of immune tolerance [14,26]. Here, Rapa-imDC preconditioning attenuated IFN-γ-producing T cell (Th1) differentiation.…”

“…As a subset of CD4 + T cells, Tregs (also known as CD4 + CD25 + Foxp3 + Tregs) can protect the host from autoimmunity by suppressing the proliferation and/or function of various immune cells, including natural killer cells, CD8 + T cells and CD4 + Th1 cells. Accumulating research has confirmed a potential application of Tregs for translation rejection by promoting postoperative immunosuppression reactivity [14,15]. …”

mTOR Signaling Inhibition Modulates Macrophage/Microglia-Mediated Neuroinflammation and Secondary Injury via Regulatory T Cells after Focal Ischemia

“…Hence, the unchanged IL-10 level might reflect a balance between the effects of IL-2/IL-2R signaling and mTOR inhibition. Researchers have observed rapamycin-induced TGF-β production by lymphocytes and infiltrated Tregs in previous studies (63, 64). Hence, rapamycin might directly increase TGF-β production in Tregs through unknown molecular mechanisms.…”

Tolerance in liver transplantation: Biomarkers and clinical relevance

“…Patients treated with rapamycin before an allergenic corneal transplant showed an increased percentage of regulatory T-cells after transplantation[130], these changes were associated with inhibition of graft rejection. In another[128], patients treated with everolimus maintained constant levels of CD4+ T-cells during the treatment, but patients treated with CNI showed a decrease of these cells.…”