Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
Solid organ transplantation is a life-saving procedure to treat end-stage organ failure. However, transplantation of organs between genetically distinct individuals results in acute graft rejection by the immune system unless patients take immunosuppressive drugs for the rest of their lives. Induction of graft acceptance in the absence of chronic immunosuppressive therapy remains an elusive goal in organ transplantation. For the first time, we have generated an animal model to overcome this formidable challenge. This finding are based on our recent manuscripts under review in the Journal of Clinical investigation (JCI). We are specifically studying the Tec kinase IL2-inducible T-cell kinase (ITK) which regulates activation of T cells by regulating signaling via the T-cell receptor (TCR) and has been shown to be involved in the activation of intracellular calcium signaling pathways, MAPK pathways, and polarization of actin cytoskeleton, supporting an integral role for ITK in T-cell activation and function. We show that T cells with a genetic ITK deficiency that exhibit attenuated T cell receptor signaling capacities and also exhibited reduced expression of IRF4 and downregulated JAK/STAT signaling, but preserved cytotoxicity which was accompanied by upregulation of transcription factors Eomes and T-bet expression which are required for tumor and viral clearence. Based on these results, we hypothesize that ITK-deficient hosts will also not reject transplanted skin and will clear opportunistic infection due to attenuated TCR signaling and higher expression of the transcription factor Eomesodermin (Eomes).
*Methods: In this study, we adopted a murine model of complete mismatch full thickness skin transplant by grafting dorsal skin from BALB/c mice to C57BL/6J background wild type or Itk knockout mice. We also perform syngeneic skin transplant as control from Balb/C to Balb/C mice. Furthermore, we used RAG-1-deficient mice as control.
*Results: Our data revealed skin transplanted from BALB/c mice to C57BL/6J was acutely rejected, but skin from BALB/c mice to ITK deficient mice in C57BL/6J background were accepted as shown in control mice BALB/c mice to BALB/c mice and BALB/c mice to RAG-1-deficient mice. We and others have shown that ITK deficient mice clear tumor and Lymphocytic choriomeningitis virus (LCMV).Currently we are performing histology and immunohistochemistry to evaluate further mechanism of graft acceptance by ITK deficient mice and skin graft rejection by WT mice. This therapeutic approaches could be applied to other organ transplants, like liver and kidneys.
*Conclusions: Altogether, our data suggest that ITK inhibition could be used as therapy for acceptance organ transplant while preserving the beneficial anti-viral effects T cells.
To cite this abstract in AMA style:Mammadli M, Karimi M, Mahmudlu S, August A, Huang W. Modulating ITK Signaling Facilitate Allogeneic Skin Engraftment and Clear LCMV Viruses by Regulating IRF-4, JAK STAT and Eomes Expression [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/modulating-itk-signaling-facilitate-allogeneic-skin-engraftment-and-clear-lcmv-viruses-by-regulating-irf-4-jak-stat-and-eomes-expression/. Accessed November 24, 2020.
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