Advances in cellular and molecular immunology have provided new opportunities for defining the mechanisms operative in the control of persistent virus infections, for developing immune-based therapies for progressive infection in immunocompromised hosts, and for the rational design and testing of vaccines to prevent or modulate infection. Cytomegalovirus (CMV) is an important cause of prenatal infection and infection in immunocompromised hosts. CD8+ class I MHC-restricted cytotoxic T cells are thought to have a decisive role in controlling CMV infection and deficiencies permit progressive infection. However, CMV is endowed with genes that function to interfere with class I antigen presentation and eliciting T cell responses of the desired specificity and magnitude pose a significant challenge for CMV vaccine development. Recent studies using a strain of CMV that is deleted in the genes that interfere with class I presentation and can display all potentially relevant epitopes from the viral proteome, demonstrate that the CD8+ T cell response to CMV In immunocompetent CMV individuals is more complex than previously appreciated. The results suggest there are additional immunodominant CMV antigens that may be essential to consider in the development of cell therapy or vaccination for CMV. The proposed experiments are designed to identify novel CMV antigens recognized by CD8+ CTL, elucidate their role in controlling CMV infection in normal CMV+ individuals, and determine if adoptive transfer of CMV-specific T cell clones can restore protective immunity in haploidentical stem cell transplant recipients.
The specific aims are: 1. To identify cytomegalovirus genes encoding novel antigens recognized by CD8+ CMV-specific cytotoxic T cells. 2. To determine the frequency and function of CD8+ T cells specific for individual CMV antigens in healthy CMV+ individuals with protective immunity. 3. To determine if adoptively transferring CMV-specific T cell clones to recipients of T cell depleted haploidentical stem cell transplant (SCT) is safe, restores CMV-specific immunity, and mediates antiviral activity.
|Jensen, Michael C; Riddell, Stanley R (2015) Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol 33:9-15|
|Berger, Carolina; Sommermeyer, Daniel; Hudecek, Michael et al. (2015) Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer Immunol Res 3:206-16|
|Jensen, Michael C; Riddell, Stanley R (2014) Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 257:127-44|
|Berger, Carolina; Berger, Michael; Beard, Brian C et al. (2013) Proliferation-linked apoptosis of adoptively transferred T cells after IL-15 administration in macaques. PLoS One 8:e56268|
|Green, Margaret L; Leisenring, Wendy M; Xie, Hu et al. (2013) CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood 122:1316-24|
|McGoldrick, Suzanne M; Bleakley, Marie E; Guerrero, Abraham et al. (2013) Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo. Blood 121:2796-803|
|Goodridge, Jodie P; Lee, Ni; Burian, Aura et al. (2013) HLA-F and MHC-I open conformers cooperate in a MHC-I antigen cross-presentation pathway. J Immunol 191:1567-77|
|Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J et al. (2013) HLA engineering of human pluripotent stem cells. Mol Ther 21:1232-41|
|Guerrero, Abraham; Riddell, Stanley R; Storek, Jan et al. (2012) Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation. Biol Blood Marrow Transplant 18:66-75|
|Berger, C; Berger, M; Anderson, D et al. (2011) A non-human primate model for analysis of safety, persistence, and function of adoptively transferred T cells. J Med Primatol 40:88-103|
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