Mechanisms and therapies of B7x and B7-H3 in T1D T cell co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. Therefore these pathways are very attractive therapeutic targets. In addition to the long-standing pathway of B7-1/B7-2/CD28/CTLA-4, we and others have discovered several additional members of the B7/CD28 families over the last several years, including B7h/ICOS, PD- L1(B7-H1)/PD-L2(B7-DC)/PD-1, B7-H3/receptor(s), B7x(B7-H4 or B7S1)/receptor(s), and HHLA2/TMIGD2/receptors. Type 1 diabetes (T1D) is an autoimmune disease characterized by infiltration of lymphocytes into the islets of the pancreas and then breakdown of glucose homeostasis as a result of destruction of insulin-producing ? cells by T cells. The incidence of T1D has risen steadily. Little is known about the roles of B7x and B7-H3 in the regulation of T cell function in peripheral non-lymphoid organs such as the pancreas where T1D occurs. Based on our recently published work and our exciting preliminary data, we have hypothesized in this proposal that B7x and B7-H3 are coinhibitors of effector T cells in T1D and are new therapeutic targets. This hypothesis will be tested by pursuing three specific aims: 1) Specific Aim 1: Dissect the mechanisms by which B7x inhibits T1D development; 2) Specific Aim 2: Determine the physiologic roles of B7-H3 in T1D; and 3) Specific Aim 3: Assess the therapeutic efficacy in T1D by targeting the B7x and B7-H3 pathways. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and achieve our goals.

Public Health Relevance

The proposed research is relevant to public health and NIH's mission, because our program will not only define the roles of the B7x and B7-H3 pathways in type 1 diabetes but also translate to new therapy opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK100525-04
Application #
9540852
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2015-09-25
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Cheng, Haiying; Borczuk, Alain; Janakiram, Murali et al. (2018) Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers. Clin Cancer Res 24:1954-1964
Sankin, Alexander; Narasimhulu, Deepa; John, Peter et al. (2018) The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1. Urol Oncol 36:459-468
Ohaegbulam, Kim C; Liu, Weifeng; Jeon, Hyungjun et al. (2017) Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells. Oncotarget 8:82740-82753
Janakiram, Murali; Shah, Urvi A; Liu, Weifeng et al. (2017) The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev 276:26-39
Cheng, Haiying; Janakiram, Murali; Borczuk, Alain et al. (2017) HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status. Clin Cancer Res 23:825-832
Koirala, Pratistha; Roth, Michael E; Gill, Jonathan et al. (2016) Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci Rep 6:30093
Liu, Weifeng; Almo, Steven C; Zang, Xingxing (2016) Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go? Immunol Invest 45:813-831
Janakiram, Murali; Pareek, Vipul; Cheng, Haiying et al. (2016) Immune checkpoint blockade in human cancer therapy: lung cancer and hematologic malignancies. Immunotherapy 8:809-19
Koirala, Pratistha; Roth, Michael E; Gill, Jonathan et al. (2016) HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival. Sci Rep 6:31154
Picarda, Elodie; Ohaegbulam, Kim C; Zang, Xingxing (2016) Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin Cancer Res 22:3425-3431

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