Nat.Rev.Immuno：树突状细胞和移植免疫耐受的研究综述

发表在最新一期《自然免疫学综述》上的一篇文章，系统地讨论了树突状细胞在移植免疫耐受中的作用。在这篇综述中，研究人员整合了各种有用的关于树突状细胞在移植中诱导免疫耐受作用的资料。

FIGURE 1 | Roles of CD8^- (myeloid) and CD8 ⁺ DCs of mouse secondary lymphoid organs in T-cell immunity and peripheral tolerance.

The diagram incorporates observations from numerous studies, mainly on splenic dendritic cells (DCs) in mice, which are the most complete source of information on natural DCs in vivo. After exposure to danger signals and/or activation and maturation stimuli, immature splenic CD8^- DCs of the red pulp and marginal zone mobilize to the T-cell areas of the spleen and, like the CD8 ⁺ DCs that reside constitutively in the T-cell areas, increase the surface expression of MHC and co-stimulatory molecules (CD80/CD86), the secretion of interleukin-12p70 (IL-12p70) and enhance their ability to stimulate naive or memory T cells. The interaction between CD154 (also known as CD40L), which is expressed transiently by activated T cells, and CD40 on the DC surface induces further activation and maturation of both DC subsets. CD8^- mature DCs might induce the expansion of regulatory T cells as an inhibitory loop to restrain the T-cell response and/or as a mechanism to prevent the breach of peripheral tolerance against those self antigens presented simultaneously with the foreign antigen by the same mature DC. By contrast, in the steady state (tolerance), CD8^- and CD8 ⁺ DCs remain quiescent after capturing and processing exogenous antigen (throughthe internalization of apoptotic cells, vesicles and/or soluble molecules — the last of which has been shown elegantly in experimental models by fusing the antigen to antibodies that specifically target different subsets of DCs in vivo^{101, 102}. These quiescent (semi-mature) DCs express low levels of co-stimulatory molecules and therefore induce deficient activation of naive T cells, and induce T-cell apoptosis or anergy and probably the generation and/or expansion of regulatory T cells. The interaction of surface CD80/CD86 on both splenic DC subsets with cytotoxic T-lymphocyte antigen 4 (CTLA4; which can be soluble in the form of the CTLA4–immunoglobulin fusion protein (not shown) or membrane-bound on regulatory T cells) enhances the synthesis of functional indoleamine 2,3-dioxygenase (IDO). IDO is an enzyme that catalyzes the depletion of the essential amino acid tryptophan, resulting in the inhibition of T-cell proliferation, and produces tryptophan-derived metabolites that promote T-cell apoptosis. IDO synthesis by CD8 ⁺ DCs requires autocrine release of interferon- (IFN ) and is inhibited by autocrine secretion of IL-6, a cytokine that downregulates expression of the IFN -receptor (IFNGR) chain CD119. Splenic CD8 ⁺ DCs express the functional CD95 ligand (CD95L), which can trigger T-cell death.

原文出处：

Nature Review Immunology  August 2007 Vol 7 No 8

Tolerogenic dendritic cells and the quest for transplant tolerance

Adrian E. Morelli & Angus W. Thomson

p610 | doi:10.1038/nri2132

Tolerogenic dendritic cells (DCs) have potential as therapeutic tools for preventing transplant rejection. This Review describes what constitutes a tolerogenic DC, how tolerogenic DCs can be induced, the mechanisms by which they mediate tolerance and the future challenges facing DC-based immunotherapy.

作者简介：

Angus W. Thomson , Ph.D., D.Sc.
Professor

Department of Immunology

Research Interests

• Understanding the role of dendritic cells in liver transplant tolerance. Here we seek to elucidate the role of dendritic leukocytes, - highly specialized antigen-presenting cells, in determining the balance between organ transplantation tolerance and immunity. Studies involve elucidation of the roles of key signaling molecules in the dialogue between dendritic cells (DC) and T cells, and investigation of the function of DC in organ allograft models.
• Genetic engineering of dendritic cells for transplantation tolerance. Using different vector delivery systems (retroviral/adenoviral), engineering dendritic cells to express genes encoding immunosuppressive molecules, including viral interleukin-10, Fas Ligand, and CTLA4Ig. Adoptive transfer of these cells to allogeneic hosts and their interaction with host T lymphocytes may promote tolerance induction, while minimizing the undesirable systemic effects of the immunosuppressive molecules.
• Monitoring tolerance in human transplant recipients. Selected techniques including dendritic subset analysis and quantification of allospecific T cell responses in vitro and in vivo are being applied with the aim of establishing assays that correlate with and are predicative of transplantation tolerance.

Education

• B.Sc. (Hons) - University Aberdeen (1970)
• M.Sc. - University Birmingham (Birmingham, UK - 1971)
• Ph.D. - University Aberdeen (1974)
• D.Sc. - University Aberdeen (1986)

Academic Affiliation

• Professor of Surgery, Immunology and Molecular Genetics & Biochemistry, University of Pittsburgh School of Medicine
• Director of Transplant Immunology, Thomas E. Starzl Transplantation Institute
• Member, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center
• Member, University of Pittsburgh Cancer Institute

Publications

• Hackstein H, and Thomson AW. (2004) Dendritic cells: emerging pharmacologic targets of immunosuppressive drugs. Nature Reviews Immunology. 4:24-34.
• Morelli AE and Thomson AW (2003) Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunological Reviews. 196:125-146.
• Hackstein H, Taner T, Zahorchak AF, Morelli AE, Logar AJ and Thomson AW. (2003) Rapamycin inhibits IL-4-induced dendritic cell maturation in vivo and dendritic cell mobilization and function in vivo. Blood. 101:4457-63.
• Morelli AE, Larregina A, Shufesky WJ, Zahorchak AF, Logar AJ, Papworth GD, Wang Z, Watkins SC, Falo LD and Thomson AW. (2003) Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and impact on cytokine production. Blood 101:611-20.
• Mazariegos GV, Zahorchak AF, Reyes J, Ostrowski L, Zeevi A, and Thomson AW. (2003) Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am J Transplantation 3:689-96.

Adrian Morelli