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Plasmacytoid Dendritic Cells Are Key Regulators of Immune Tolerance

Matta, Benjamin (2012) Plasmacytoid Dendritic Cells Are Key Regulators of Immune Tolerance. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Solid organ allograft rejection and many autoimmune disorders remain significant clinical problems despite the efficacy of current immunosuppressive (IS) drug treatments. Moreover, the side effects of global IS drugs that inhibit immune responses in a non-specific manner may leave the host susceptible to development of cancer and chronic infection. The need for antigen (Ag)-specific treatments to reduce or eliminate the need for IS drugs is merited in these cases.
Dendritic cells (DC) are important Ag-presenting cells (APC) that mediate innate and adaptive immune responses, and have been widely investigated as potential cell-based therapeutics to bolster or supplant current IS drug treatments in transplantation and autoimmune diseases. Conventional (c)DC are the most potent APC, however, they can be modified and conditioned to instead modulate immune responses and promote Ag-specific tolerance. Plasmacytoid (p)DC, the primary cells that produce type I IFN and activate anti-viral immunity, are also recognized as holding significant tolerogenic potential. In this dissertation, I present novel data that support the tolerogenic function of pDC and highlight their inability to elicit strong immune responses in the absence of viral infection. pDC exhibit a more immature phenotype compared to cDC that correlates to their weak ability to stimulate T cells. Moreover, liver pDC are less mature compared to pDC in the spleen. They promote regulatory T cell function, suppress delayed-type hypersensitivity responses, and are critical for the spontaneous acceptance of murine liver allografts. My data show that the co-inhibitory molecule B7 homolog-1 (B7-H1) is important for the immune regulatory capacity of spleen and liver pDC, and that the cytokine IL-27 regulates critical inhibitory functions of liver pDC, including their expression of B7-H1 and their immune suppressive capacity in vitro and in vivo.
In summary, my data provide evidence that pDC are an attractive target for development of cell-based therapies and identify novel mechanisms utilized by pDC to regulate immune reactivity. I have described for the first time that donor pDC contribute to the spontaneous acceptance of murine liver allografts, a discovery that has important implications for development of future therapeutics to promote immune tolerance, especially in solid organ transplantation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Matta, Benjaminbmm24@pitt.eduBMM24
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorThomson, Angusthomsonaw@upmc.eduATHOMSON
Committee MemberKane, Lawrencelkane@pitt.eduLKANE
Committee MemberMorelli, Adrianmorelliae@upmc.eduMORELLI
Committee MemberLakkis, Fadilakkisf@upmc.eduFGL1
Committee MemberRay, Anuradharaya@pitt.eduRAYA
Committee MemberDeFrances, Mariedefrancesmc@upmc.eduMCD14
Date: 15 August 2012
Date Type: Publication
Defense Date: 27 June 2012
Approval Date: 15 August 2012
Submission Date: 24 July 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 178
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 Cells, Plasmacytoid, Tolerance, Transplantation, Cytokines, Liver, Regulation
Date Deposited: 15 Aug 2012 12:01
Last Modified: 19 Dec 2016 14:38


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