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Identification of heme oxygenase-1–specific regulatory CD8+ T cells in cancer patients
Journal of Clinical Investigation, 07/16/09

Andersen MH et al. - Identification of potent antigen-specific CD8+ Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer.

Exclusive Author Commentary
Mads Hald Andersen, 08/03/09

Regulatory elements are essential for the homeostasis of the immune system. While regulatory CD4+ T cells have received much attention over the past years, less is known about regulatory CD8+ T cells; moreover, antigens recognized by these cells remain unknown. In the present study we tested the hypothesis that Tregs specific antigens are derived from proteins that are expressed in the late phase of inflammatory reactions and which contribute in a critical manner to inhibit or terminate inflammation. Heme oxygenase-1 (HO-1) has a vital immune protective effect and HO-1 is extensively expressed in various tumor cells. The upregulation of HO-1 in cancer cells combined with its anti-inflammatory effects prompted us to scrutinize if regulatory T cells specifically recognizing HO-1 are present in cancer patients. To this end, HO-1 specific, HLA-A2 restricted, CD8+ T-cells were detected ex vivo and in situ in high frequencies and – most notably - these cells were able to suppress cells immune responses with an unparalleled efficacy. The presence of HO-1 specific CD8+ Tregs inhibited the antigen-specific cytokine release, proliferation and cytotoxicity of other cells of the immune system. Moreover, only 500 directly isolated HO-1 specific CD8+ T cells had a superior suppressive effect on CD4+ and CD8+ lymphocytes compared to between 25.000-50.000 conventional CD4+/CD25high/CD127- Tregs isolated from the same patients. The inhibitory activity of these cells seems at least partly to be mediated by soluble factors. The first identification of antigen specific CD8+ regulatory T cells and the outstanding capacity of these cells to suppress immune responses open new opportunities for therapeutic intervention to modulate immune responses. In the clinical setting the induction of specific suppressor immune responses, e.g. by vaccination or adoptive transfer of specific T cells, could suppress rejection of transplanted organs or graft-versus-host disease after allogenic stem cell transplantation. Similarly, such therapeutic measures could be employed to treat autoimmune diseases. On the other hand, the presence of such antigen specific regulatory T cells in the tumor microenvironment must be regarded as an obstacle for the development of effective anti-cancer immune responses. Moreover, it is very likely that the detection of HO-1 specific regulatory CD8+ Tregs may represent a general phenomenon. Hence, other proteins of similar protective and anti-inflammatory function as HO-1 could represent targets for natural occurring Tregs.

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