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Dissertation
Virus-specific cytotoxic effector cell function and the genetic regulation of cytokine production during E-55+ murine leukemia virus infection
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Apr 2001
DOI:
https://doi.org/10.17918/00007912
Abstract
Infection of inbred mice with E-55+ MuLV results in an acute viremia with infected cells in the spleen. Following this acute phase, an asymptomatic persistent E-55+ MuLV infection is established. Mice susceptible to E-55+ MuLV-induced disease, progressors (P), develop a leukemia/lymphoma following the persistent phase of infection. Mice that are resistant to progression, non-progressors (NP), maintain an asymptomatic infection. The P and NP strains differ in their T-cell requirement in order to establish an asymptomatic infection and P strains lack anti-virus T-cell responses capable of preventing the re-emergence of E-55+ MuLV-infected cells. The role of E55+ MuLV-specific cytotoxic T lymphocytes (CTLs) and their function as well as the genetic regulation of IL-4 (which affects T-cell function) was investigated. It was determined that P, BALB/c-H-2b (BALB. B), mice display only a transient E-55+ MuLV-specific cytotoxic effector response, whereas NP, C57BL/6 (H-2b), mice display E-55+ MuLV-specific cytotoxic effector function during both acute and persistent infecton. Two of five perforin deficient C57BL/6 mice were unable to maintain an asymptomatic persistent E-55+ MuLV infection after one year, suggesting that CTL function is important in the maintenance of an asymptomatic persistent E-55+ MuLV infection. The lack of detectable E-55+ MuLV-specific CTLs in persistently infected BALB. B (P) mice can be restored by co-culture with "helper" cells. The "helper" population requires the presence of CD3+ cells in order to restore anti-virus effector function. Thus, a reversible loss of E-55+ MuLV-specific cytotoxic effector function may be responsible for the inability of the P to prevent E-55+ MuLV replication in vivo during persistent infection. Cytokine profiles of P and NP splenocytes differ during the acute phase of E-55+ MuLV infection. The stimulation of splenocytes results in the production of type 0 cytokines (IL-4 and IFN-[gamma]) in BALB (P) strains and type 1 cytokines (IFN-[gamma] and no IL-4) in C57BL (NP) strains. The production of IL-4 is a recessive phenotype, and analysis of backcross mice estimates that it is controlled by two loci. In addition, linkage analysis of CXB recombinant inbred strains displays linkage with markers on chromosomes 3, D3Mit51 , and 11, D11Mit338. Candidate loci include il-12a and cd-7.
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Details
- Title
- Virus-specific cytotoxic effector cell function and the genetic regulation of cytokine production during E-55+ murine leukemia virus infection
- Creators
- Christopher Scott Little
- Contributors
- Kenneth J. Blank (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- x, 100 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021889011004721