Vaccination-Induced Autoimmune Vitiligo Is a Consequence of Secondary Trauma to the Skin

Abstract

A major concern for cancer vaccines targeting self-tumor antigens is the risk of autoimmune sequelae. Although antitumor immunity correlates with autoimmune disease in some preclinical models, the mechanism(s) linking antitumor immunity and subsequent autoimmune pathology remain(s) to be determined. In the current study, we demonstrated that intradermal (i. d

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…We have previously reported that immunization with a recombinant adenovirus (Ad) expressing human dopachrome tautomerase (DCT; also as known as tyrosinase-related protein-2) could induce CD4 1 T-cell-mediated tumor protection and autoimmune vitiligo, independent of CD8 1 T cells [1]. In the present study, we demonstrate that anti-tumor effector functions in this model are IL-4 and STAT6-dependent, whereas autoimmunity requires IFN-g and STAT4 signaling.…”

“…Although studies by our group and others have demonstrated that protection following immunization with DCT is mediated primarily by T cells [1,4], it is nevertheless possible that under extreme conditions, such as CD8 1 T-cell depletion, a role for antibodies as effectors may emerge. To confirm that the CD4-dependent, CD8-independent immune protection was due to CD4 1 T-cell effector function and not simply due to their role as helpers for B-cell differentiation, we tested CD8-depleted, B-cell-deficient (B À/À ) mice for induction of anti-tumor immunity and autoimmune vitiligo.…”

“…We have previously reported that immunization with AdhDCT could protect C57BL/6 mice against a lethal B16F10 melanoma challenge and autoimmune vitiligo [1]. Interestingly, tumor protection and vitiligo induction were abrogated only by in vivo depletion of both CD4 1 and CD8 1 T cells at the effector phase, while depletion of either subset alone did not affect the outcome of the two events, suggesting that CD4 1 T cells are efficient in mediating tumor and normal tissue destruction in the absence of CD8 1 T cells.…”

“…Using a murine melanoma model, we and others have demonstrated that the development of effective anti-tumor immunity also results in autoimmune depigmentation (manifested as vitiligo) and this appears to be true for both T-cell-and antibody-mediated mechanisms [1,4]. Concomitant development of anti-tumor immunity and autoimmune pathology appears to occur more readily when there is trauma/inflammation within the skin or the vaccination method is intensified [1]. These results suggest that vaccine-associated autoimmune destruction may not be avoidable, especially when there is a concurrent inflammatory event in healthy tissues that express antigens carried by the vaccine.…”

“…Although it has been suggested that breaking selftolerance through successful application of cancer vaccines will inevitably result in autoimmune sequelae, the true relationship between anti-tumor and autoimmune pathology remains uncertain [1][2][3]. Using a murine melanoma model, we and others have demonstrated that the development of effective anti-tumor immunity also results in autoimmune depigmentation (manifested as vitiligo) and this appears to be true for both T-cell-and antibody-mediated mechanisms [1,4]. Concomitant development of anti-tumor immunity and autoimmune pathology appears to occur more readily when there is trauma/inflammation within the skin or the vaccination method is intensified [1].…”