Microchimerism, dendritic cell progenitors and transplantation tolerance

Abstract

Abstract. The recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrowderived dendritic cell (DC). These cells have been classically perceived as the most potent antigenpresenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GM-CSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to T -dependent areas of host lymphoid tissue, where some at least up regulate cell surface MHC class II. These donor-derived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver.Correspondence: Dr.

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

“…These findings complement older reports that graft-derived dendritic cells (DC) traffic to both draining and systemic lymphoid organs to present alloantigen (43,44). Our studies suggest that secondary lymphoid organs are equally important for the induction of tolerance.…”

“…For example, anti-CD40L mAb causes significant and prolonged changes in splenic germinal center architecture (46). More durable approaches to tolerance, such as microchimerism, may also require analysis of lymphoid organ structure (44). Our hypothesis suggests that chimeric interactions in the LN may be germane for tolerance, or that donor CD62L Ϫ/Ϫ hemopoietic cells may be unable to induce tolerance.…”

TGF-β1 gene-modified, immature dendritic cells delay the development of inflammatory bowel disease by inducing CD4+Foxp3+ regulatory T cells

“…19 Furthermore, imDCs can also induce allograft tolerance, suggesting a solution to allograft rejection. 20 TGF-b1 is a key factor during the differentiation of Th cells, which can upregulate Foxp3 expression in Th0 cells, driving them to differentiate into CD4 1 Foxp3 1 Tregs. 16 Here, we successfully transferred the TGF-b1 gene into bone marrowderived imDCs by using adenovirus, and detected a high level of Figure 3 In vitro function of TGF-b1-DCs.…”

Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients

“…DC that are inherently deficient in cell surface expression of costimulatory molecules can induce T cell hyporesponsiveness in vitro and prolong allograft survival. 24 In this study, we have shown that myeloid DC propagated in vitro with GM-CSF + IL-4 can be transduced using a replication-deficient Ad vector to express the gene encoding CTLA4Ig. This chimeric fusion protein is a potent immunosuppressant that blocks the expression of B7 costimulatory molecules on APC [5][6][7] and that suppresses both experimental allograft rejection [12][13][14][15] and autoimmune disease.…”