Maintenance of Immune Tolerance Depends on Normal Tissue Homeostasis

Abstract

Ags expressed at immune privileged sites and other peripheral tissues are able to induce T cell tolerance. In this study, we analyzed whether tolerance toward an intraocular tumor expressing a highly immunogenic CTL epitope is maintained, broken, or reverted into immunity in the event the anatomical integrity of the eye is lost. Inoculation of tumor cells into the anterior chamber of the eye of naive B6 mice leads to progressive intraocular tumor growth, an abortive form of CTL activation in the tumor-draining submandibular lymph node, and systemic tolerance as evidenced by the inability of these mice to reject an otherwise benign tumor cell inoculum. Loss of anatomical integrity of the eye as a consequence of phthisis resulted in loss of systemic tolerance and the emergence of effective antitumor immunity against an otherwise lethal tumor challenge. Phthisis was accompanied by dendritic cell maturation and preceded the induction of systemic tumor-specific CTL immunity. Our data show that normal tissue homeostasis and anatomical integrity is required for the maintenance of ocular tolerance and prevention of CTL-mediated immunity. These data also indicate that tissue injury in the absence of viral or microbial infection can act as a switch for the induction of CTL immunity.

The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits

“…In addition, a small fraction of animals with either MHC or multiple minor mismatched islets in our study appeared tolerant, and this may be due to the increased graft healing time compared to previous studies where tolerance was not observed [18]. More detailed studies will be required to determine the precise contribution of tissue 'health' or homeostasis [2,3,40,41] in any tolerance generated with pre-immunocompetence transplants. Interestingly, we found greater acceptance of MHC mismatched compared to multiple minor-H mismatched pre-immunocompetence islet transplants; a result that is consistent with an increased importance for the indirect pathway in triggering the anti-donor response to long-healed transplants, where a paucity of donor antigen-presenting cells is expected [42-44].…”

Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages

“…One potential explanation is that SPLNX influences tumor-specific CD8 + T cell numbers within intraocular tumors. Consistent with that notion, Boonman and coworkers demonstrated that another tumor cell line (Ad5E1 plus EJ-ras) transplanted in the a.c. of the eye formed progressively growing tumors in 40% of B6 mice whereas the remaining mice spontaneously eliminated tumors by a CD8 T cell-dependent process that culminated in phthisis (35, 36). Although tumor growth in both progressor and regressor mice induced expansion of tumor-specific CD8 + T cells in draining lymph nodes, only regressor mice showed systemic dissemination of these effector CD8 + T cells.…”

Cancer Immunotherapy by Dendritic Cells

“…DC phenotypes in cancer tissue and cancer-draining lymph nodes are often those corresponding to resting, nonactivated, ''immature'' DCs, both in tumor-bearing animals and in patients with cancer (reviewed in Gabrilovich, 2004;Schuurhuis et al, 2006a;Dhodapkar et al, 2008) (van Mierlo et al, 2004Boonman et al, 2005) Early studies have suggested that patients with high numbers of DCs present in tumors survived longer than patients with few or no DCs in the cancer tissue (Becker, 1993). However, in a more recent study, colorectal cancer patients with relatively high numbers of ''mature'' CD208 + -infiltrating DCs in the tumor epithelium had a markedly shorter survival rate (Sandel et al, 2005).…”