Getting a Handle on Graft-versus-Host Disease
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《新英格兰医药杂志》
A central dichotomy of allogeneic hematopoietic stem-cell transplantation for neoplastic diseases is that the immune responses initiated by donor-derived cells provide both the chief benefit and the major limitation of the therapy. The benefit is the graft-versus-tumor (GVT) effect, and the limitation is graft-versus-host disease (GVHD). Edinger and his colleagues1 have reported a method for overcoming the limitation. They prevented GVHD while preserving the GVT effect in a mouse model of lymphoma by including CD4+CD25+ regulatory T lymphocytes in the inoculum of hematopoietic stem cells.
The immune response represents the net effect of factors that stimulate the immune system and those that suppress or regulate it. Initially, research focused on factors that stimulate immune responses, but the importance of regulatory functions is now clear.
Two populations of regulatory T lymphocytes are type 1 T regulatory (Tr1) cells, which secrete cytokines, and CD4+CD25+ T lymphocytes, which exert their regulatory effect through cell–cell contact.2,3 How do CD4+CD25+ T regulatory lymphocytes allow GVT activity while they suppress the GVHD response? One possibility is that the GVT effect is mediated by cells other than T lymphocytes; this is the case in hematopoietic stem-cell transplantation for acute myeloid leukemia, wherein natural killer cells are critical. However, Edinger et al. found that tumor cells were killed by T lymphocytes, which suggests the following scenario (Figure 1).
Figure 1. Sparing the Host while Killing the Tumor.
In graft-versus-host disease, donor-derived naive CD25– T lymphocytes are stimulated by the recipient's antigen-presenting cells and thus initiate graft-versus-host disease. The regulatory CD4+CD25+ T lymphocytes react with costimulatory molecules (CD80 and CD86) on the recipient's antigen-presenting cells; the regulatory T lymphocytes can then inhibit the expansion of T lymphocytes. In the graft-versus-tumor effect, naive CD25– T lymphocytes can respond to tumor-associated antigens expressed on tumor cells, even though the tumor cells have variable expression or no expression of CD80 or CD86. However, the reduced expression of these costimulatory molecules is insufficient to trigger the activation of CD4+CD25+ T lymphocytes, and so the expansion of the tumor-specific T lymphocytes can proceed unchecked.
After infusion, naive CD25– T lymphocytes are activated by the histocompatibility antigen expressed on the recipient's antigen-presenting cells; if these activated lymphocytes are not regulated, they can trigger GVHD. At the same time, CD4+CD25+ T lymphocytes interact with both histocompatibility antigens on the recipient's antigen-presenting cells, which also express the costimulatory molecules CD80 and CD86 — hence, the CD4+CD25+ T lymphocytes become activated. These activated cells then suppress the proliferation of T lymphocytes and thus prevent GVHD.
As for the GVT effect, it seems that tumor cells are unable to stimulate the activation of functional regulatory CD4+CD25+ T lymphocytes, probably because they have a patchy expression, if any, of the costimulatory molecules CD80 and CD86. The tumor cells, however, can usually stimulate a tumor-specific response mediated by T lymphocytes. The unchecked proliferation of these antitumor lymphocytes results in the GVT effect.
Edinger et al.1 used a one-to-one ratio between the transplanted regulatory T lymphocytes and naive CD4+CD25+ T lymphocytes. The ratio does not mimic normal physiology, in which CD4+CD25+ T lymphocytes represent only 6 to 7 percent of peripheral CD4+ T lymphocytes. Thus, to use this approach clinically, CD4+CD25+ regulatory T lymphocytes must be isolated and expanded.
There are always questions about the clinical applicability of studies in mice. Nevertheless, a better understanding of human CD4+CD25+ and other regulatory T lymphocytes has the potential to improve the treatment of neoplastic and other diseases, as demonstrated by the study by Edinger et al.1
Source Information
From the Saban Research Institute, Children's Hospital, Los Angeles.
References
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-1150.
Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001;182:68-79.
Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317-5326.(Robertson Parkman, M.D.)
The immune response represents the net effect of factors that stimulate the immune system and those that suppress or regulate it. Initially, research focused on factors that stimulate immune responses, but the importance of regulatory functions is now clear.
Two populations of regulatory T lymphocytes are type 1 T regulatory (Tr1) cells, which secrete cytokines, and CD4+CD25+ T lymphocytes, which exert their regulatory effect through cell–cell contact.2,3 How do CD4+CD25+ T regulatory lymphocytes allow GVT activity while they suppress the GVHD response? One possibility is that the GVT effect is mediated by cells other than T lymphocytes; this is the case in hematopoietic stem-cell transplantation for acute myeloid leukemia, wherein natural killer cells are critical. However, Edinger et al. found that tumor cells were killed by T lymphocytes, which suggests the following scenario (Figure 1).
Figure 1. Sparing the Host while Killing the Tumor.
In graft-versus-host disease, donor-derived naive CD25– T lymphocytes are stimulated by the recipient's antigen-presenting cells and thus initiate graft-versus-host disease. The regulatory CD4+CD25+ T lymphocytes react with costimulatory molecules (CD80 and CD86) on the recipient's antigen-presenting cells; the regulatory T lymphocytes can then inhibit the expansion of T lymphocytes. In the graft-versus-tumor effect, naive CD25– T lymphocytes can respond to tumor-associated antigens expressed on tumor cells, even though the tumor cells have variable expression or no expression of CD80 or CD86. However, the reduced expression of these costimulatory molecules is insufficient to trigger the activation of CD4+CD25+ T lymphocytes, and so the expansion of the tumor-specific T lymphocytes can proceed unchecked.
After infusion, naive CD25– T lymphocytes are activated by the histocompatibility antigen expressed on the recipient's antigen-presenting cells; if these activated lymphocytes are not regulated, they can trigger GVHD. At the same time, CD4+CD25+ T lymphocytes interact with both histocompatibility antigens on the recipient's antigen-presenting cells, which also express the costimulatory molecules CD80 and CD86 — hence, the CD4+CD25+ T lymphocytes become activated. These activated cells then suppress the proliferation of T lymphocytes and thus prevent GVHD.
As for the GVT effect, it seems that tumor cells are unable to stimulate the activation of functional regulatory CD4+CD25+ T lymphocytes, probably because they have a patchy expression, if any, of the costimulatory molecules CD80 and CD86. The tumor cells, however, can usually stimulate a tumor-specific response mediated by T lymphocytes. The unchecked proliferation of these antitumor lymphocytes results in the GVT effect.
Edinger et al.1 used a one-to-one ratio between the transplanted regulatory T lymphocytes and naive CD4+CD25+ T lymphocytes. The ratio does not mimic normal physiology, in which CD4+CD25+ T lymphocytes represent only 6 to 7 percent of peripheral CD4+ T lymphocytes. Thus, to use this approach clinically, CD4+CD25+ regulatory T lymphocytes must be isolated and expanded.
There are always questions about the clinical applicability of studies in mice. Nevertheless, a better understanding of human CD4+CD25+ and other regulatory T lymphocytes has the potential to improve the treatment of neoplastic and other diseases, as demonstrated by the study by Edinger et al.1
Source Information
From the Saban Research Institute, Children's Hospital, Los Angeles.
References
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-1150.
Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001;182:68-79.
Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317-5326.(Robertson Parkman, M.D.)