Host-derived Langerhans cells persist after MHC-matched allografting independent of donor T cells and critically influence the alloresponses mediated by donor lymphocyte infusions. (57/429)

Mouse models of minor histocompatibility Ag-mismatched bone marrow transplantation were used to study donor dendritic cell (DC) reconstitution after conditioning, variables influencing the persistence of residual host DCs in different compartments, their phenotype, and their role in governing donor lymphocyte infusion (DLI)-mediated alloresponses. Reconstitution of all splenic DC subsets occurred rapidly after bone marrow transplantation and before T cell reconstitution. However, in contrast to MHC-mismatched chimeras, residual host-derived DCs persisted in the cutaneous lymph nodes (CLNs) of MHC-matched chimeras despite the presence or addition of donor T cells to the graft. The phenotype of these residual host-derived DCs in CLNs was consistent with Langerhans' cells (LCs). We confirmed their skin origin and found near-complete preservation of host-derived LCs in the skin. Host-derived LCs retained their ability to continuously traffic to the CLNs, expressed homogeneously increased levels of costimulatory molecules, and could capture and carry epicutaneously applied Ags. To determine the role of residual host LCs in governing DLI-mediated alloresponses, we administered DLI alone or after topical application of the TLR7 ligand imiquimod, which is known to enhance the LC emigration from the skin. DLI administration resulted in a decrease in host-derived DCs in the CLNs and increased recruitment of donor-derived DCs to the skin, whereas imiquimod augmented their alloreactivity. These results suggest uniqueness of the MHC-matched setting in relation to the persistence of host-derived DCs in the skin and points to a previously unrecognized role of host-derived LCs in the induction of DLI-mediated graft-vs-host alloresponses.  (+info)

Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects. (58/429)

Coincidence of the beneficial graft-vs.-tumor (GVT) effects and the detrimental graft-vs.-host disease (GVHD) remains the major obstacle against the widespread use of allogeneic bone marrow transplantation (BMT) as tumor immunotherapy. We here demonstrate that intervention of MAdCAM-1 (mucosal vascular addressin cell adhesion molecule-1) or fractalkine/CX3CL1 after the expansion of allo-reactive donor CD8 T cells selectively inhibits the recruitment of effector donor CD8 T cells to the intestine and alleviates the graft-vs.-host reaction (GVHR) associated intestinal injury without impairing GVT effects. In a nonirradiated acute GVHD model, donor CD8 T cells up-regulate the expression of intestinal homing receptor alpha4beta7 and chemokine receptors CXCR6 and CX3CR1, as they differentiate into effector cells and subsequently infiltrate into the intestine. Administration of anti-MAdCAM-1 antibody or anti-fractalkine antibody, even after the expansion of alloreactive donor CD8 T cells, selectively reduced the intestine-infiltrating donor CD8 T cells and the intestinal crypt cell apoptosis without affecting the induction of donor derived anti-host CTL or the infiltration of donor CD8 T cells in the hepatic tumor. Moreover, in a clinically relevant GVHD model with myeloablative conditioning, these antibodies significantly improved the survival and loss of weight without impairing the beneficial GVT effects. Thus, interruption of alpha4beta7-MAdCAM-1 or CX3CR1-fractalkine interactions in the late phase of GVHD would be a novel therapeutic approach for the separation of GVT effects from GVHR-associated intestinal injury.  (+info)

Chimerism in systemic lupus erythematosus--three hypotheses. (59/429)

Systemic lupus erythematosus (SLE) is an immune-mediated disease characterized by the presence of autoantibodies and a wide array of clinical symptoms. Despite intensive research, the aetiology of SLE is still unknown and is probably multifactorial. Both genetic and environmental factors have been associated with SLE, but these factors alone are insufficient to explain the onset of SLE. Recently, it has been suggested that chimerism plays a role in the pathogenesis of autoimmune diseases, including SLE. Chimerism indicates the presence of cells from one individual in another individual. In an experimental mouse model, the injection of chimeric cells induces a lupus-like disease. In addition, chimerism is found more often in kidneys of women with SLE than in healthy controls. There are several mechanisms by which chimeric cells could be involved in the pathogenesis of SLE. In this review, three hypotheses on the role of chimerism in SLE are discussed. The first two hypotheses describe the possibilities that chimeric cells induce either a graft-vs-host reaction in the host (comparable with reactions seen after bone marrow transplantation) or a host-vs-graft reaction (comparable with reactions seen after solid organ transplantation). The third hypothesis discusses the possible beneficial role chimeric cells may play in repair mechanisms due to their stem cell-like properties. This review provides insights into the mechanisms by which chimerism may be involved in SLE and proposes several lines of inquiry to further investigate chimerism in SLE.  (+info)

Factors governing the activation of adoptively transferred donor T cells infused after allogeneic bone marrow transplantation in the mouse. (60/429)

Murine models of bone marrow transplantation were used to study the mechanisms governing the activation of donor lymphocyte infusions (DLIs) manifesting as lymphohematopoietic graft-versus-host (LH-GVH) and graft-versus-leukemia (GVL) reactivities. We demonstrate here that established mixed chimerism influences the potency of DLI-mediated alloreactivity only in the MHC-mismatched but not MHC-matched setting. In the MHC-matched setting, high levels (>or= 40%) of residual host chimerism correlated negatively with DLI-mediated alloreactivity irrespective of the timing of their administration, the donor's previous sensitization to host antigens, or the level of residual host APCs. In vivo administration of Toll-like receptor (TLR) ligands was required to maximize DLI-mediated LH-GVH and GVL reactivities in chimeras with low levels (+info)

Hematopoietic cell transplantation: progress and obstacles. (61/429)

The use of hematopoietic cell transplantation has expanded and evolved substantially in the last decade. New stem cell sources and stem cell mobilizing agents have been introduced in clinical practice. The incidence of life-threatening complications following autologous stem cell transplant procedures has decreased dramatically. Understanding the immune mediated effect of allogeneic stem cell transplantation has resulted in the development of reduced intensity and non-myeloablative conditioning regimens, allowing transplantation of elderly patients. Long-term complications are starting to emerge, and will gain in importance in the near future.  (+info)

Absence of donor T-cell-derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity. (62/429)

Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.  (+info)

The role of interferon alpha/beta in the induction of intestinal pathology in mice. (63/429)

We have investigated the role of interferon-alpha/beta (IFN-alpha/beta) and IFN-dependent effector cells in causing enteropathy in mice. The IFN-inducer polyinosinic:polycytydylic acid (poly I:C) augmented the natural killer (NK) cell activation normally seen in neonatal (CBA x BALB/c)F1 mice with graft-versus-host reaction (GVHR) and exacerbated the systemic and intestinal consequences of GVHR. Poly I:C itself produced a similar pattern of intestinal pathology when administered to normal mice. The effects of poly I:C on NK cell activity and intestinal architecture in normal mice could be reproduced by a single injection of purified IFN-alpha/beta and the intestinal lesions caused by IFN-alpha/beta were prevented by in vivo depletion of NK cells with anti-asialo GM1. These results indicate that IFN-alpha/beta may play an important role in immunologically mediated enteropathies by virtue of its ability to activate NK cells.  (+info)

Expression of allograft inflammatory factor-1 in inflammatory skin disorders. (64/429)

Allograft inflammatory factor-1 (AIF-1) is an evolutionarily conserved, inflammatory protein produced by activated macrophages during chronic transplant rejection and in inflammatory brain lesions. Since T-cell-mediated inflammation is common to various dermatoses and nothing is known about AIF-1 in skin, we studied its protein expression at the tissue level and regulation in monocytic cell lines by various agents. Using immunohistochemistry, we found that AIF-1 is expressed at low levels in normal skin, but is highly upregulated in various inflammatory skin disorders, such as psoriasis, lichen planus, graft-versus-host disease and mycosis fungoides. The main cell types expressing AIF-1 in affected skin are macrophages and Langerhans' cells. We also show by real-time PCR that AIF-1 mRNA levels in monocytic THP-1 and U937 cell lines are significantly upregulated by retinoic acid as well as a number of cytokines. We conclude that AIF-1 may mediate survival and pro-inflammatory properties of macrophages in skin diseases.  (+info)