Donor dendritic cell persistence in organ allograft recipients in the absence of immunosuppression

O’Connell, Peta J.; Burlingham, William J.

doi:10.1002/jlb.66.2.301

Cited by 16 publications

(13 citation statements)

References 41 publications

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“…However, it is noted that there exist CXCL16-expressing infiltrating cells in the tolerated grafts (Fig. 3) as previously reported by several investigators that APCs, including dendritic cells and macrophages which can express CXCL16 (9,(12)(13)(14), are migrated into long-surviving allografts (23). The existence of CXCL16-expressing cells in the tolerated allografts indicates that there is an inflammation to some extent, which is in line with the observation that sole CD40L blockade therapy cannot prevent chronic rejection of the allografts (24).…”

Section: Adhesion Of Nkt Cells To Membrane-bound Cxcl16supporting

confidence: 82%

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

Jiang

Shimaoka

Kojo

et al. 2005

The Journal of Immunology

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It is well-documented that certain chemokines or their receptors play important roles in the graft rejection. However, the roles of chemokines and their receptors in the maintenance of transplantation tolerance remain unclear. In this study, we demonstrate that blocking of the interaction between the chemokine receptor, CXCR6, highly expressed on Vα14+ NKT cells and its ligand, CXCL16, resulted in the failure to maintain graft tolerance and thus in the induction of acceleration of graft rejection. In a mouse transplant tolerance model, the expression of CXCL16 was up-regulated in the tolerated allografts, and anti-CXCL16 mAb inhibited intragraft accumulation of NKT cells. In vitro experiments further showed that blocking of CXCL16/CXCR6 interaction significantly affected not only chemotaxis but also cell adhesion of NKT cells. These results demonstrate the unique role of CXCL16 and CXCR6 molecules in the maintenance of cardiac allograft tolerance mediated by NKT cells.

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Section: Adhesion Of Nkt Cells To Membrane-bound Cxcl16supporting

confidence: 82%

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

Jiang

Shimaoka

Kojo

et al. 2005

The Journal of Immunology

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“…It is recognized that donor-derived APCs residing in the interstitium of allografts, in particular macrophages and DCs, are instigators of primary allospecific immune responses via direct alloantigen presentation to recipient responder cells within secondary lymphatic tissue 11,14,39 . However, due to their potent ability to instigate an adaptive immune response by activating naïve T cells, DCs are generally regarded as primary initiators of allograft rejection 39,40 .…”

Section: Discussionmentioning

confidence: 99%

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

et al. 2015

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Background Organ transplantation has seen an increased utilization of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplant outcomes when utilizing older donor organs represent a growing challenge. Methods and Results Here, we characterize the impact of donor age on solid organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when utilizing older hearts. Shorter graft survival of older hearts was independent of organ age per se, as chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells (DCs) augmenting CD4+ and CD8+ T cell proliferation and pro-inflammatory cytokine production, particularly that of IL-17A. Of note, depletion of donor CD11c+ DCs prior to engraftment, neutralization of IL-17A or transplantation of older hearts into IL-17A-/- mice delayed rejection and reduced alloimmune responses to levels observed when transplanting young hearts. Conclusions These results demonstrate a critical role of old donor CD11c+ DCs in mounting age-dependent alloimmune responses with an augmented IL-17A response in recipient animals. Targeting IL-17A may serve as a novel therapeutic approach when transplanting older organs.

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“…A number of studies have focused on the importance of ongoing Ag exposure and/or of tolerogenic DCs in maintenance of allograft survival (22), with recent studies suggesting that indirect Ag presentation can break graft tolerance, while in tolerant animals, direct Ag presentation can suppress rejection (29). Some of the altered development of DCs is apparently a reflection of the altered cytokine milieu in the transplanted tissue that, along with CD200-CD200R interactions, can control the status of monocyte differentiation, promoting in vitro induction of Tregs and/or in vivo protection from autoimmune diseases (18).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that improved acceptance of skin allografts in mice was associated with increased expression of a number of distinct mRNAs, one of which encoded CD200, a molecule expressed on the surface of dendritic cells DCs 3 (4,12); that using a soluble immunoadhesin (CD200Fc), in which the extracellular domain of CD200 was linked to a murine IgG2aFc region, or in mice which overexpression of a transgenic CD200 was under control of a doxycycline (Dox)-inducible promoter, inhibition of T cell allostimulation and type 1 cytokine production (IL-2, IFN-␥) occurred in vitro and in vivo (13,14); and that CD200-mediated immunoregulation reflected signaling following an interaction with receptors, CD200Rs, on the surface of myeloid and or lymphoid cells (15)(16)(17), which could in turn favor development of "tolerogenic" DCs and/or regulatory T cells (Tregs) that were implicated in enhanced graft survival (18,19). A large and growing body of work confirms the importance of Tregs in transplantation tolerance (20,21) and the interrelatedness of this with DC function (22)(23)(24).…”

mentioning

confidence: 99%

Expression of a CD200 Transgene Is Necessary for Induction but Not Maintenance of Tolerance to Cardiac and Skin Allografts

Gorczynski

Chen

et al. 2009

The Journal of Immunology

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CD200, a type 2 transmembrane molecule of the Ig supergene family, can induce immunosuppression in a number of biological systems, as well as promote increased graft acceptance, following binding to its receptors (CD200Rs). Skin and cardiac allograft acceptance are readily induced in transgenic mice overexpressing CD200 under control of a doxycycline-inducible promoter, both of which are associated with increased intragraft expression of mRNAs for a number of genes associated with altered T cell subset differentiation, including GATA-3, type 2 cytokines (IL-4, IL-13), GITR, and Foxp3. Interestingly, some 12–15 days after grafting, induction of transgenic CD200 expression can be stopped (by doxycycline withdrawal), without obvious significant effect on graft survival. However, neutralization of all CD200 expression (including endogenous CD200 expression) by anti-CD200 mAb caused graft loss, as did introduction of an acute inflammatory stimulus (LPS, 10 μg/mouse, delivered by i.p. injection). We conclude that even with apparently stably accepted tissue allografts, disruption of the immunoregulatory balance by an intense inflammatory stimulus can cause graft loss.

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Donor dendritic cell persistence in organ allograft recipients in the absence of immunosuppression

Cited by 16 publications

References 41 publications

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

Expression of a CD200 Transgene Is Necessary for Induction but Not Maintenance of Tolerance to Cardiac and Skin Allografts

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Donor dendritic cell persistence in organ allograft recipients in the absence of immunosuppression

Cited by 16 publications

References 41 publications

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

Cutting Edge: Critical Role of CXCL16/CXCR6 in NKT Cell Trafficking in Allograft Tolerance

CD11c + Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A

Expression of a CD200 Transgene Is Necessary for Induction but Not Maintenance of Tolerance to Cardiac and Skin Allografts

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CD11c ⁺ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A