Reovirus administered to the gut mucosal surface will be used to probe the roles of the cellular components of the murine gut associated lymphoid tissue (GALT) in preventing, limiting, containing, and resolving viral infections that commence via the intestinal route. Conventionally reared, germfree, neonatal, and severe combined immunodeficient (SCDD) mice will be used as hosts. Reoviruses are extremely effective at stimulating both mucosal B cell and specific cytotoxic (CD8) T cell responses. Thus, they provide model infections for defining the protective specific and non-specific cellular components that one should expect to be primed by an effective attenuated viral vaccine given orally. We will seek to establish any developmental interrelationship between precursor cytotoxic CD8+ lymphocytes (pCTLs) in Peyer's patches (PP) and the intraepithehal lymphocyte (IEL) compartment and to evaluate the persistence and turnover of specific pCTLS at both of these sites. We will investigate the roles of specific IELs at protecting vs. and limiting viral infection in the gut and whether GALT compartments such as PP and IEL are functionally linked via the homing receptors borne by their cellular constituents. The development and functional potential of subsets of specific CD4+ T cells in the different compartments of GALT will be examined by in vivo turnover studies using BrdU and in vitro microculture for both frequencies and ability to interact with B cells to promote the expression of particular Ig isotypes, such as IgA. Both specific CD8+ and CD4+ cells from GALT and systemic tissue will be further analyzed for fine specificities and in vivo function to address two unresolved concerns of practical significance: 1) whether virus processing and presentation by the gut route is substantially different than when it is introduced parenterally; and 2) whether the phenomenon of systemic tolerance and contrasuppression associated with oral immunization with some antigens extends to virus infections? Finally, using the SCID mouse as a model host that suffers fatal consequences of oral infection with reovirus due to liver failure, we will further attempt to clarify the role of natural killer (NK) cells acting in the IEL compartment or in the liver. Particularly, we will seek to define the bases for their accumulation in infected liver, target cell preferences, contributions to liver pathology, and interactions with adoptively transferred T cell subsets in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI023970-06
Application #
3136594
Study Section
Experimental Virology Study Section (EVR)
Project Start
1986-08-01
Project End
1996-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zuercher, Adrian W; Coffin, Susan E; Thurnheer, M Christine et al. (2002) Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses. J Immunol 168:1796-803
Zuercher, Adrian W; Jiang, Han-Qing; Thurnheer, M Christine et al. (2002) Distinct mechanisms for cross-protection of the upper versus lower respiratory tract through intestinal priming. J Immunol 169:3920-5
Kushnir, N; Bos, N A; Zuercher, A W et al. (2001) B2 but not B1 cells can contribute to CD4+ T-cell-mediated clearance of rotavirus in SCID mice. J Virol 75:5482-90
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Periwal, S B; Cebra, J J (1999) Respiratory mucosal immunization with reovirus serotype 1/L stimulates virus-specific humoral and cellular immune responses, including double-positive (CD4(+)/CD8(+)) T cells. J Virol 73:7633-40
Cebra, J J; Periwal, S B; Lee, G et al. (1998) Development and maintenance of the gut-associated lymphoid tissue (GALT): the roles of enteric bacteria and viruses. Dev Immunol 6:13-8
Major, A S; Rubin, D H; Cuff, C F (1998) Mucosal immunity to reovirus infection. Curr Top Microbiol Immunol 233:163-77
Periwal, S B; Speaker, T J; Cebra, J J (1997) Orally administered microencapsulated reovirus can bypass suckled, neutralizing maternal antibody that inhibits active immunization of neonates. J Virol 71:2844-50

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