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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PTM-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
Watkin, Levi B; Mishra, Rabinarayan; Gil, Anna et al. (2017) Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. J Allergy Clin Immunol 140:1206-1210
Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2017) Heterologous Immunity and Persistent Murine Cytomegalovirus Infection. J Virol 91:
Aslan, Nuray; Watkin, Levi B; Gil, Anna et al. (2017) Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires. MBio 8:
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
Hasgur, Suheyla; Aryee, Ken Edwin; Shultz, Leonard D et al. (2016) Generation of Immunodeficient Mice Bearing Human Immune Systems by the Engraftment of Hematopoietic Stem Cells. Methods Mol Biol 1438:67-78
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
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 138:769-779
Cohen, Jessica L; Shen, Yuefei; Aouadi, Myriam et al. (2016) Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA. Mol Pharm 13:964-978
Tencerova, Michaela; Aouadi, Myriam; Vangala, Pranitha et al. (2015) Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB J 29:2959-69
Gil, Anna; Yassai, Maryam B; Naumov, Yuri N et al. (2015) Narrowing of human influenza A virus-specific T cell receptor ? and ? repertoires with increasing age. J Virol 89:4102-16

Showing the most recent 10 out of 118 publications