COSTIMULATORY MOLECULE-DEFICIENT DENDRITIC CELL PROGENITORS (MHC CLASS II+, CD80dim, CD86-) PROLONG CARDIAC ALLOGRAFT SURVIVAL IN NONIMMUNOSUPPRESSED RECIPIENTS12
| Autor: | Fumin Fu, Youping Li, Thomas E. Starzl, John J. Fung, Shiguang Qian, Frances G. Chambers, Lina Lu, Angus W. Thomson |
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| Rok vydání: | 1996 |
| Předmět: |
Graft Rejection
Male Lymphoid Tissue Mice Inbred Strains Lymphocyte Activation Article Immunophenotyping Mice Antigens CD Animals Progenitor cell Interleukin 4 Immunosuppression Therapy CD86 Transplantation MHC class II Membrane Glycoproteins biology Stem Cells Graft Survival Histocompatibility Antigens Class II Granulocyte-Macrophage Colony-Stimulating Factor CD28 Dendritic Cells Dendritic cell Stimulation Chemical Immunology B7-1 Antigen biology.protein Heart Transplantation B7-2 Antigen Interleukin-4 Lymphocyte Culture Test Mixed CD80 T-Lymphocytes Cytotoxic |
| Zdroj: | Transplantation. 62:659-665 |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/00007890-199609150-00021 |
| Popis: | The discovery in 1992 of multilineage leukocyte microchimerism many years after organ transplantation (1, 2) implied the migration and survival of donor progenitor or even stem cells within recipient tissues. A prominent donor leukocyte, both in these clinical observations and in experimental animal studies (3, 4), has been the dendritic cell (DC*). These bone marrow (BM)-derived leukocytes are the most potent known antigen-presenting cells (APC). They have the unique capacity to activate resting, naive T lymphocytes (5). In addition, however, tolerogenic properties of DC have been described both in vitro (6, 7) and in vivo (8, 9). Recently, we reported that donor-derived DC progenitors can be propagated in vitro from the BM of unmodified mice that permanently accept MHC-incompatible liver transplants, but not from the lymphoid tissue of animals that acutely reject heart grafts (10). The in vivo functional relevance of donor-derived DC progenitors has not been established. It has been suggested that, in sufficient numbers, these chimeric APC may play a role in the induction of transplantation tolerance (1-4, 10, 11). The functional maturation of DC and other APC, such as macrophages or activated B cells, has been shown to depend on the cytokine-induced up-regulation of cell surface MHC class II and T-cell“costimulatory” molecules, particularly the CD28 ligands B7-1 (CD80) and B7-2 (CD86) (12, 13). We hypothesized that in accordance with the “two-signal” hypothesis of T-cell activation (14), failure of MHC class II+ DC progenitors to deliver essential costimulatory signals might result in a state of induced unresponsiveness (anergy). DC propagated from normal mouse BM in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin (IL)-4 (“mature” DC) are potent inducers of allogeneic T-cell activation. In contrast, costimulatory molecule-deficient DC progenitors (MHC class II+, B7-1dim, B7-2-) grown in low concentrations of GM-CSF alone fail to stimulate in primary mixed leukocyte reactions (MLR) and induced donor-specific T-cell anergy (15). In this study, we have examined the relevance of these findings to organ transplantation by administering costimulatory molecule-deficient DC progenitors to normal mice that subsequently received vascularized cardiac allografts. The data show that pretreatment with these donor-derived cells 1 week before transplant prolongs graft survival. Moreover, injection of DC progenitors is associated at the time of transplant with hyporesponsiveness of host T cells to donor alloantigens. In all cases, hyporesponsiveness to a third party was also observed. The eventual graft rejection may be ascribed to in vivo upregulation of costimulatory molecule expression on donor-derived DC in the absence of exogenous immunosuppression. |
| Databáze: | OpenAIRE |
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