General autoimmunity

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Mechanisms Driving an Autoimmune-like Syndrome in Humanized Mice

Thursday, June 15
5:45 PM - 7:00 PM

Spontaneous development of a graft-versus-host disease (GVHD)/autoimmunity syndrome after around 25-40 weeks post-transplantation limits the experimental window for humanized mice generated by transplantation of human hematopoietic stem cells (HSCs) with/without a human thymus to immunodeficient NOD/SCID/gamma (NSG) mice. The cause of this disease is unknown. Skin, lungs, spleen, liver and intestine are infiltrated with mononuclear cells, neutrophils and histiocytes. Target organs and the lymphoid tissues of affected mice contained very high levels of CD4 and CD8 effector/memory cells, suggesting that the disease targets antigens presented on both MHC classes I and II. Measures were taken to exhaustively deplete pre-existing thymocytes and analysis of infiltrates in animals with different thymus vs HSC donors indicated that the T cell infiltrates were largely HSC-derived. Thymectomized NSG recipients, which fail to develop human T cells, did not develop autoimmunity/GVHD. Humanized mice constructed with an intact native mouse thymus, which supports a low thymic output, demonstrated earlier disease onset (20-45 weeks) compared to mice with thymocyte-depleted human thymus grafts (35-60 weeks) that support higher thymic output. Adoptive transfer of T cells to T cell-deficient mice with autologous human APCs, revealed that human APC-dependent lymphopenia-induced proliferation (LIP) of T cells significantly accelerated disease onset. In conclusion, while both mouse and human thymi produce T cells causing this syndrome, more prominent LIP of T cells developing in mouse thymus accelerated the disease, whose etiology may be multifactorial.

Mohsen Khosravi Maharlooei

Columbia Center for Translational Immunology, Columbia University

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    Markus Hoelzl

    Columbia Center for Translational Immunology, Columbia University

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      Haowei Li

      Columbia Center for Translational Immunology, Columbia University

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        Aditya Misra

        Columbia Center for Translational Immunology, Columbia University

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          Guiling Zhoa

          Columbia Center for Translational Immunology, Columbia University

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            Grace Nauman

            Columbia Center for Translational Immunology, Columbia University

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              Megan Sykes

              Columbia Center for Translational Immunology, Columbia University

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