Student Theses and Dissertations

Date of Award

2008

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Nussenzweig Laboratory

Abstract

Dendritic cells (DCs) play a pivotal role in determining whether the outcome of the immune system's encounter with antigen will be immunity or tolerance. Using an antibody against the DEC-205 receptor, antigens have been delivered specifically to DCs in vivo. Under steady state conditions, such presentation of antigen leads to peripheral tolerance in transgenic T cells, either by deletion, anergy or the induction of regulatory T cells. We wanted to examine whether delivery of autoantigens to DCs using this approach, could be used to tolerize autoreactive polyclonal T cells, thereby preventing autoimmunity in mouse models. We succeeded in inducing tolerance to the myelin oligodendrocyte protein and preventing disease in the experimental autoimmune encephalomyelitis model. However no halt or delay in onset of autoimmune diabetes was observed when insulin was targeted to DCs in the non-obese diabetic (NOD) mouse model. Also, foreign antigen-specific T cell responses could not be abolished by targeting antigen to DCs in the NOD mouse. These results strongly suggested that establishing peripheral tolerance in disease-prone polyclonal repertoires such as in the NOD model, would be far more challenging than the previously studied tolerance in non-autoreactive transgenic models had been. We recognized that success in DC-targeting-based autoimmune therapy would first require a better understanding of tolerance in non-disease prone polyclonal T cell repertoires. Towards that end, we examined T cell tolerance in C57BL/6 mice. In the steady state, targeting ovalbumin (OVA) to DCs resulted in polyclonal CD4 and CD8 T cell tolerance. This tolerance was non-deletional and characterized by persistence of T cells that produced IFNγ, but no IL-2. CD4 dependent antibody production by B cells in vivo was abrogated. Also, both CD4 and CD8 proliferative responses in vitro were abolished. Subsequent to tolerization, depending on the strength of the costimulatory stimulus that the CD4 and CD8 T cells are exposed to, tolerance can be reversed both in vivo and in vitro. Thus our results demonstrate that while tolerance in non-autoreactive polyclonal repertoires in steady state DC environments can be achieved, reversal of the tolerized state can also occur. This suggests that in autoreactive T cell repertoires in chronically inflamed DC environments, the prevention or treatment of autoimmune disease is a challenge that will require comprehensive understanding of the balance between immunity and tolerance.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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