The major effort in our lab has been to develop and translate novel therapies to prevent and reverse adverse immune repsonses, with the ultimate goal of clinical translation, for example, in monogenic diseases like hemophilia A (HA), but also in autoimmunity and allergy. These tolerogenic approaches include B-cell delivery of Fc-fusion proteins and nanoparticles that we have shown can lead to the activation of antigen-specific regulatory T cells (Tregs). During the last four years, our focus in HA has emphasized the production and validation of novel engineered specific regulatory T cells that express either a FVIII-specific T-cell receptor (TCR) or a single chain variable fragment (scFv) chimeric receptor (Kim et al., 2015, Yoon et al. 2017). The TCR-transduced Tregs are MHC-restricted and recognize FVIII-peptide on antigen-presenting cells. On the other hand, scFv-expressing Tregs (CAR-like) respond to conformational epitopes on cell surfaces. Recently, we developed an additional approach to inhibit/kill the FVIII-specific B-cells that give rise to plasma cells, using both Tregs and CD8+ T cells that express FVIII domains (Zhang et al. 2018). We named the latter cells ?BAR? for B-cell-targeting Antibody Receptor. The latter T cells express a chimeric receptor (CAR), comprised of a protein antigen or its domain, linked with the transmembrane and signal transduction domains, CD28-CD3?, like the above two CARs. The three types of engineered chimeric receptor T cells can strongly block the anti- FVIII immune response in vitro and in vivo, and recent data suggest that BAR Tregs can suppress the symptoms of anaphylaxis in the presence of circulating antibody. Based on the success of our approaches, our goals in this renewal are to further analyze and optimize the ability of these different engineered Tregs to suppress not only primary but also ongoing anti-FVIII responses in vitro and in vivo. We will also analyze the cellular targets and molecular mechanisms by which these engineered T cells suppress specific antibody formation in hemophilic mice as well as in B-cell receptor transgenics. Evaluating their long-term efficacy in vivo in the presence of circulating antibody is an important goal. These studies will provide proof of principle for the utility and mechanism of action of engineered Tregs and provide steps for clinical translation.

Public Health Relevance

Our lab has focused on developing approaches to prevent or even reverse adverse immune responses, such as inhibitor formation to therapeutic factor VIII in hemophilia. We have previously engineered human regulatory T lymphocytes (called Tregs) with antigen-specificity to induce tolerance to modulate these adverse immune responses. In this proposal, we will analyze three novel murine Tregs specific for FVIII. We will determine their function in the presence of inihibitors and study their stability and mechanism of action, and as a step for future clinical translation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Sarkar, Rita
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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Sicard, Antoine; Levings, Megan K; Scott, David W (2018) Engineering therapeutic T cells to suppress alloimmune responses using TCRs, CARs, or BARs. Am J Transplant 18:1305-1311
Kim, Yong Chan; Kim, Kee Kwang; Yoon, Jeongheon et al. (2018) SAMHD1 Posttranscriptionally Controls the Expression of Foxp3 and Helios in Human T Regulatory Cells. J Immunol 201:1671-1680
Zhang, Ai-Hong; Yoon, Jeongheon; Kim, Yong Chan et al. (2018) Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells. J Immunol 201:1434-1441
Blumberg, Richard S; Lillicrap, David; IgG Fc Immune Tolerance Group (2018) Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia Blood 131:2205-2214
Parvathaneni, Kalpana; Abdeladhim, Maha; Pratt, Kathleen P et al. (2017) Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy. Transl Res 187:44-52
Yoon, Jeongheon; Schmidt, Anja; Zhang, Ai-Hong et al. (2017) FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood 129:238-245
Adair, Patrick R; Kim, Yong Chan; Zhang, Ai-Hong et al. (2017) Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision. Front Immunol 8:1117
Adair, Patrick; Kim, Yong Chan; Pratt, Kathleen P et al. (2016) Avidity of human T cell receptor engineered CD4(+) T cells drives T-helper differentiation fate. Cell Immunol 299:30-41