Viral infections pose a threat to patients receiving allogeneic transplants because of the immunosuppressive drug regimens used to prevent graft rejection. For this reason alternative schemes involving the induction of immunological tolerance have been developed as an alternative strategy to selectively but not globally tolerize a patient. We have developed both peripheral and central tolerization regimens in mice using antibody (anti-CDI 54) approaches that are successful in establishing long term tolerance to allogeneic grafts. These mice can maintain their grafts and eventually effectively control virus infections. However, in the first few weeks after tolerization, these mice and their grafts are vulnerable to infection, and we propose the following specific aims to understand how infections with several experimental viruses, including lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (W), murine cytomegalovirus (MCMV), and influenza A virus (lAV), can disrupt the maintenance of transplantation tolerance during this vulnerable period. With Project 1 we are also developing additional CDI 54 RNA knock down approaches to tolerize mice. The overall hypotheses to be supported or refuted in this Project 2 are that heterologous cross-reactive immunity, as opposed to bystander activation, is responsible forthe virus-induced abrogation ofthe maintenance of peripheral tolerance, that T regulatory cells may modulate this process, and that viruses are threats to centrally tolerized hosts and the maintenance of their grafts.

Public Health Relevance

It is well-documented that viral infections are major threats to the survival of grafts of transplant patients and that immunosuppressive drug therapy given to prevent graft rejection makes patients susceptible to such infections. This was recently illustrated in the deaths of transplantation patients receiving grafts from a patient unknowingly infected with LCMV. Here we examine alternative tolerization schemes and how these grafts are impacted by viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046629-13
Application #
8473765
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$288,733
Indirect Cost
$102,377
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9
Bryce, Paul J; Falahati, Rustom; Kenney, Laurie L et al. (2016) Humanized mouse model of mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. J Allergy Clin Immunol 138:769-79
Cohen, Jessica L; Shen, Yuefei; Aouadi, Myriam et al. (2016) Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA. Mol Pharm 13:964-78
Samanta, S; Sun, H; Goel, H L et al. (2016) IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 35:1111-21
Presa, Maximiliano; Chen, Yi-Guang; Grier, Alexandra E et al. (2015) The Presence and Preferential Activation of Regulatory T Cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T Cell Effectors into NSG versus NOD-scid Mice. J Immunol 195:3011-9
Trabucco, Sally E; Gerstein, Rachel M; Evens, Andrew M et al. (2015) Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res 21:113-22
Babad, J; Mukherjee, G; Follenzi, A et al. (2015) Generation of β cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin Exp Immunol 179:398-413
Gil, Anna; Kenney, Laurie L; Mishra, Rabinarayan et al. (2015) Vaccination and heterologous immunity: educating the immune system. Trans R Soc Trop Med Hyg 109:62-9
Nayar, Ribhu; Schutten, Elizabeth; Jangalwe, Sonal et al. (2015) IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection. PLoS One 10:e0144826
Che, Jenny W; Selin, Liisa K; Welsh, Raymond M (2015) Evaluation of non-reciprocal heterologous immunity between unrelated viruses. Virology 482:89-97

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