Core C provides a critical means by which the PPG will achieve its goals of understanding the in vivo functions of pathways in the B7:CD28 family individually, the interactions among these pathways, and their roles in regulating the balance between pathogenic and protective T cells in lymphoid and non-lymphoid organs. This Core will provide PPG investigators with an important and unique collection of mouse strains for the analysis of pathways in the B7:CD28 family in vivo and has the expertise with both conventional and conditional transgenic and knockout technology that will enable the generation of novel mouse strains for analyzing the functions of these pathways in vivo.
Our specific aims are: 1) To generate novel mouse strains lacking CD28 or B7 family members, conditionally or inducibly, 2) To generate transgenic strains that overexpress B7:CD28 family members, either constitutively or inducibly 3) To generate mouse strains that facilitate the analysis of interactions between negative regulatory receptors or the interplay between positive and negative second signals in the B7:CD28 family, 4) To generate mouse strains that facilitate the analysis of roles of B7:CD28 family members in regulating the balance between protective and pathogenic immune responses by breeding mice lacking or overexpressing B7 or CD28 family members with cytokine, cytokine receptor, and FoxPS reporter strains, and 5) To maintain and provide mice of existing transgenic and knockout strains to PPG investigators. Core C will work closely with project investigators, not only to provide them with transgenic and knockout strains, but also to generate novel strains based upon their findings in PPG projects. Core C also will provide mice lacking B7 and CD28 family members to Core B for the generation of novel mAbs and transgenic mice for studies aimed at evaluating agonistic Ig fusion proteins and mAbs that deliver a negative signal. Taken together, these activities of Core C will provide PPG investigators with novel mouse strains for studying the roles of pathways in the B7:CD28 family in cpntrolling T cell responses in mouse models of transplantation, autoimmunity, and infection. These studies will not only provide insights into the roles of these pathways in regulating T cell activation and tolerance in vivo, but also may provide information critical for therapeutic manipulation of these key immunoregulatory pathways.
These studies will provide the basis for understanding how, where and when costimulatory molecules regulate allograft rejection, organ-specific autoimmune diseases, and chronic viral infection These studies have implications for developing costimulation-based therapies for human chronic viral infections, cancer, autoimmune diseases and alloresponses that limit hematopoietic and solid organ allograft acceptance.
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|Kamphorst, Alice O; Wieland, Andreas; Nasti, Tahseen et al. (2017) Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423-1427|
|Guo, Yanxia; Walsh, Alice M; Fearon, Ursula et al. (2017) CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progression. J Immunol 198:4490-4501|
|MacDonald, Kelli P A; Hill, Geoffrey R; Blazar, Bruce R (2017) Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. Blood 129:13-21|
|Rigas, Diamanda; Lewis, Gavin; Aron, Jennifer L et al. (2017) Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction. J Allergy Clin Immunol 139:1468-1477.e2|
|Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904|
|Zhang, Ruan; Sage, Peter T; Finn, Kelsey et al. (2017) B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells. J Immunol 199:3972-3980|
|Hippen, K L; O'Connor, R S; Lemire, A M et al. (2017) In Vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines. Am J Transplant 17:3098-3113|
|Du, Jing; Paz, Katelyn; Flynn, Ryan et al. (2017) Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-? production. Blood 129:2570-2580|
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