Diabetes and other autoimmune endocrine diseases

Oral

Selective Expansion of pd-1+tigit+ cd4 T Cells Following Depletion of cd2hi Cells with Alefacept in Recent Onset t1d

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

In an ITN clinical trial, alefacept (an LFA3-Fc fusion protein targeting CD2) preserved endogenous insulin production in recent onset T1D a year following therapy cessation. Since alefacept may have deletional and agonistic effects on the immune system, we assessed lymphoid phenotypic and functional changes with therapy and developed an in vitro model mimicking alefacept mechanism of action. Immunological changes observed during treatment included 63-73 % depletion of CD2hi CD4 and CD8 memory T cells and CD56hi NK cells, preservation of Tregs, and 26-33% increases in PD-1+TIGIT+CD4 memory T cells in peripheral blood following treatment. PD1+TIGIT+ CD4 memory T cells failed to express CD57 and KLRG1, suggestive of an anergic/exhausted phenotype. Culture of alefacept with PBMCs from T1D subjects replicated depletion of CD2hi memory T cells and CD56hi NK cells including CD2hiPD1+ cells. In the same cultures, there was concomitant activation of CD56loCD16hi NK cells that correlated with a significant reduction of CD2hiCD4 effector memory cells and an increase in CD2loPD1+TIGIT+ memory CD4 T cells. To test the hypothesis that alefacept increases CD2loPD-1+TIGIT+ CD4 T cells in an agonistic manner, we performed mix-back experiments and found a 48% increase in PD-1+TIGIT+ cells in CD2loCD4 effector memory T cells. Together, these data suggest that alefacept may function through deletion of CD2hi cells and selective expansion of CD2loPD-1+TIGIT+CD4 T cells. Understanding the possible role of therapy-induced PD-1+TIGIT+ CD4 T cells, and factors that maintain their functional properties associated with hyporesponsiveness may help explain the success of alefacept therapy.

Duangchan Suwannasaen

Benaroya Research Institute at Virginia Mason

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    Katharine Schwedhelm

    Benaroya Research Institute

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      Jerill Thorpe

      Benaroya Research Institute

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        Carla Greenbaum

        Director, Diabetes Program
        Benaroya Research Institute

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          Cate Speake

          Benaroya Research Instutute

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            Jerry Nepom

            Benaroya Research Institute at Virginia Mason

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              Kristina Harris

              Immune Tolerance Network

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                S. Alice Long

                Benaroya Research Institute

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                  Selective Expansion of pd-1+tigit+ cd4 T Cells Following Depletion of cd2hi Cells with Alefacept in Recent Onset t1d



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