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Regulation by IL-10 of innate immune responses to MUC1 as a self-antigen in MUC1 transgenic mice

Marvel, Douglas M (2014) Regulation by IL-10 of innate immune responses to MUC1 as a self-antigen in MUC1 transgenic mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Immune responses against a peptide derived from the MUC1 extracellular domain are inhibited in mice which transgenically express the human tumor antigen MUC1 (MUC1.Tg mice). One of the hallmarks of this tolerance is an inability to generate robust CD4 T cell responses. However, this tolerance is not due to a lack of MUC1 specific effector T cells in these animals, as it is evident even after naïve MUC1 specific CD4 T cells have been adoptively transferred in prior to vaccination. Here we show that immediately following intravenous MUC1 vaccination in MUC1.Tg mice, splenic dendritic cell (DC) activation is suppressed. This is measureable both by reduced levels, compared to DC from vaccinated WT mice, of MHC Class II, CD40, and CD86 on the surface of these DC, as well as by the level of a new marker of DC activation: expression of traditional pancreatic enzymes. These enzymes, exemplified by trypsin 1 and carboxypeptidase B1, are up-regulated in splenic DC following MUC1 vaccination in WT, but not MUC1.Tg mice. Their suppression in MUC1.Tg mice requires the activity of both regulatory T cells and IL-10. IL-10’s role in this system appears to be antigen specific as it is produced in the spleens of MUC1 vaccinated MUC1.Tg mice at higher levels than in the spleens of similarly treated WT animals. Furthermore, removal of IL-10 signaling from the system by pretreating animals with an antibody against the IL-10 receptor prior to MUC1 vaccination increases the MUC1 specific CD4 T cell response in MUC1.Tg, but not WT mice. The cellular source of this IL-10 was identified by flow cytometry as being natural killer (NK) cells. In addition to producing IL-10, NK cells from the spleens of MUC1.Tg mice post MUC1 vaccination are more cytotoxic and poorer at maturing DC in co-culture than NK cells from similarly treated WT mice. Depletion of these NK cells improves the quality of the MUC1 specific CD4 response in MUC1.Tg mice. Together, this data identifies a number of previously unidentified early factors which are responsible for the observed inability of MUC1.tg mice to generate robust MUC1 specific CD4 T cell responses.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Marvel, Douglas Mdouglas.marvel@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorFinn, Oliveraojfinn@pitt.eduOJFINN
Committee MemberMorel, Penelope Amorel@pitt.eduMOREL
Committee MemberKane, Lawrencelkane@pitt.eduLKANE
Committee MemberSarkar, Saumendrasaumen@pitt.eduSAUMEN
Committee MemberCoyne, Carolyn Bcoynec2@pitt.eduCOYNEC2
Date: 28 April 2014
Date Type: Publication
Defense Date: 19 December 2013
Approval Date: 28 April 2014
Submission Date: 22 April 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 162
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Dendritic Cell, Natural Killer Cell, DC, NK, MUC1, IL-10, Cancer Vaccine, Prophylactic Cancer Vaccine, Peripheral Tolerance, Central Tolerance
Date Deposited: 28 Apr 2014 18:03
Last Modified: 15 Nov 2016 14:19
URI: http://d-scholarship.pitt.edu/id/eprint/21411

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