Date of Award

4-19-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

David Sherman Bradley

Abstract

Spontaneous polyarthritis (SA) is an autoimmune disease that develops spontaneously at 4 months of age in the HLA-DQ6αβ8αβ double transgenic (tg) mice. The disease is characterized by lymphocyte infiltration in joints leading to chronic polyarthritis in the extremities similar to human rheumatoid arthritis. Immature dendritic cells (iDCs) have a tolerogenic potential due to low expression of important costimulatory cell surface molecules required for antigen presentation and induction of an effective immune response. In this study it has been shown that injection of iDCs pulsed with chick type II collagen (CII) significantly delayed the onset and suppressed the severity of SA in the HLA-DQ6αβ8αβ tg mouse model. Bone marrow derived iDCs were pulsed in vitro with CII and transferred into 6 week old HLA-DQ6αβ8αβ tg mice. Mice receiving CII-pulsed iDCs did not display any clinical signs of disease until 5.5 months of age indicating the ability of the DC vaccine to significantly delay the onset of SA. The severity and incidence of disease was reduced in mice injected with CII-pulsed iDCs. In order to determine the mechanism/s of disease prevention, we studied the effect of CII-pulsed DCs on the T cell phenotype and functional analysis both in vitro and in vivo. The overall mechanism involved in the protection alter CII-pulsed iDC vaccination may be one or combinations of many. This study demonstrated that CII-pulsed mature DCs induce expansion of CD4+25 +Foxp3+ regulatory T cells in vivo and production of immunoregulatory cytokine, IL-10 in vitro increases with CII-pulsed mature DCs compared to unpulsed mature DCs. Deficient intrinsic suppression was observed in the aged and young double tg mice compared to the B10 controls. These data suggest that CII-pulsed mature DCs help in the expansion of tolerogenic or immunosuppressive phenotype of T cells. In conclusion, induced expansion of functional regulatory T cells in vivo after DC vaccination plays an important role in controlling inflammation in the SA model. This is the first evidence of DC therapy controlling SA and suggests that DC vaccination may provide a tool to reducing clinical manifestations in human inflammatory autoimmune disease such as rheumatoid arthritis.

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