Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation.
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Alemtuzumab (anti-CD52; Campath 1-H) depletes both host and donor T cells when used in preparative regimens for allogeneic transplantation. This promotes engraftment even after nonmyeloablative conditioning and limits graft-versus-host disease (GVHD) even after unrelated or major histocompatibility complex (MHC) disparate allografts. We asked whether anti-CD52 differentially targets antigen-presenting cells (APCs), in addition to depleting T cells. Monocyte-derived dendritic cells (moDCs) expressed abundant CD52 as expected. Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs), however, never expressed CD52. Immunostaining of skin and gut confirmed the absence of CD52 on these resident DC populations under both steady-state and inflammatory conditions. Although anti-CD52 functions primarily by antibody-dependent cellular cytotoxicity (ADCC) in vivo, assessment of its activity in vitro included complement-dependent lysis of CD52(+) cells. Anti-CD52 did not impair DC-T-cell adhesion, diminish DC-stimulated T-cell proliferation, or alter moDC development in vitro. We propose that anti-CD52 abrogates GVHD not only by T-cell depletion, but also by removing moDCs and their precursors. This would mitigate moDC phagocytosis and presentation of host-derived antigens to donor T cells in the inflammatory peritransplantation environment, thereby limiting GVHD. The sparing of LCs and DDC-IDCs by anti-CD52, as well as the recovery of donor-derived moDCs in a less inflammatory environment later after transplantation, may allow all these DCs to exert formative roles in graft-versus-tumor (GVT) reactions and immune reconstitution. Whether these results support a separation of deleterious from beneficial graft-host interactions at the level of antigen presentation, rather than solely at the level of T cells, will require further evaluation. (+info)
Donor T cell and host NK depletion improve the therapeutic efficacy of allogeneic bone marrow cell reconstitution in the nonmyeloablatively conditioned tumor-bearing host.
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Allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned host has the advantage that it can be tolerated in suboptimal health conditions. However, the problem of graft versus host disease (GvHD) remains. Also, graft acceptance may become delicate, and HvGD may arise. We report here on advantages/disadvantages of host natural killer (NK) depletion and graft T cell depletion in fully allogeneic, healthy and solid tumor-bearing mice. NK depletion of the "healthy" host improved the survival rate, whereas graft T cell depletion was disadvantageous. In the tumor-bearing host, graft T cell depletion was beneficial when the host was NK-depleted. Host NK depletion facilitated B lymphopoiesis, repopulation of the thymus, expansion of donor cells, and tolerance induction. The disadvantage of graft T cell depletion in the "healthy" host was a result of delayed engraftment. Because in tumor-bearing mice, host but not graft hematopoiesis was strongly impaired, donor hematopoiesis dominated. Graft T cell depletion reduced GvHD but hardly interfered with engraftment. Importantly, graft-mediated tumor reactivity appeared late and was unimpaired when the graft was T cell-depleted. Thus, concomitant depletion of host NK and donor T cells is advantageous when approaching therapeutic treatment of solid tumors by allogeneic reconstitution of the nonmyeloablatively conditioned host. (+info)
Antigens shared by malignant plasma cells and normal B cells may be involved in graft versus myeloma.
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Cytotoxic T cells play an important role in graft-versus-host-disease (GvHD) and graft-versus-leukaemia/myeloma, which may occur in patients treated with an allogeneic stem cell transplantation (ASCT). Here, we describe the selection of a myeloma reactive CD4+ cytotoxic T cell-line (CTL) and two CD4+ clones from this CTL. The CTL was generated from the blood from a patient with multiple myeloma (MM) with graft versus myeloma/GvHD, following an ASCT. The CTL was stimulated using irradiated peripheral blood mononuclear cells and EBV transformed B cells from the myeloma patient (EBVp), both of which were obtained prior to ASCT. Both the CTL and the two T cell clones specifically lysed EBVp and secreted IFN-gamma after coculture with EBVp and autologous myeloma tumour cells in a class II restricted fashion. These results show that myeloma tumour cells and autologous B cells present a common polymorphic peptide that functions as a target for graft derived cytotoxic T cells. Identification of these proteins will give insight into the relationship between graft versus myeloma (GvM) and GvHD and may provide immunotherapeutical targets in the treatment of MM. (+info)
CD8+ immunoregulatory cells in the graft-versus-host reaction: CD8 T cells activate dendritic cells to secrete interleukin-12/interleukin-18 and induce T helper 1 autoantibody.
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Initiation of cell-mediated immunity or autoimmunity requires secretion of interleukin (IL)-12 from dendritic cells (DC), which drives the generation of T helper 1 (Th1) effector cells in synergy with IL-18. Induction of IL-12 can be triggered by microbial stimuli but also requires signals from activated T cells. We investigated interactions between alloreactive CD4 and CD8 T cells in mixed lymphocyte reactions (MLR) in vitro and in the graft-versus-host reaction (GVHR) in vivo. In a parent-into-F1 model of GVHR, donor CD8 cells were found to suppress the hyper-immunoglobulin E (IgE) syndrome, anti-DNA immunoglobulin G1 (IgG1) autoantibodies and donor CD4-cell expansion, but were essential for Th1-dependent immunoglobulin G2a (IgG2a) autoantibody production and release of serum IL-12 p40. In vitro, addition of alloreactive CD8 cells to CD4 cells and mature DC enhanced Th1 development. CD4 and CD8 T cells induced IL-18 from DC and primed for IL-12 p70 secretion via interferon-gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha). However CD8 T cells, but not CD4 cells, released IFN-gamma/TNF-alpha after primary stimulation. The data suggest that rapid release of inflammatory cytokines from central memory-type CD8 cells early in immunity is critical for induction of Th1 cells via DC activation and IL-12 production. This pathway could provide a means for amplification of cell-mediated autoimmunity in the absence of microbial stimuli. (+info)
Immunity in the eye: lessons in organ-specific responses.
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Fifty-five years have past since Sir Peter Medawar first demonstrated that the fate of allografts differs in the skin, brain, subcutaneous tissue, and anterior chamber of the eye. Indeed, these and other experiments performed at the University of Birmingham and University College London not only helped define key paradigms in transplantation biology but introduced the concept of immune privilege in the eye and in other tissues. In the ensuing years, the work from dozens of laboratories has confirmed that immune responses in eye, although sharing many features with immunity in other tissues, are atypical in many respects. This has been hypothesized to stem from the requirement in the eye to hold inflammation in check to preserve visual function. Indeed, inflammatory reactions in different regions of the eye can result in visual impairment and blindness, manifesting in diseases such as vernal keratoconjunctivitis, uveitis, corneal endotheliitis, Mooren's ulcer, and pemphigoid. The investigation of the cell and molecular basis of the unique nature of immunity in the eye has revealed a remarkably complex network of interactions that controls inflammation while affording immunity. The most recent data generated in this field and the concepts arising from their interpretation were discussed at a symposium held at the University College London in late 2002. Here, we highlight some of the findings discussed at the meeting and introduce in-depth reviews published in this issue of the journal. (+info)
The immune response in cirrhotic rats. Antigen distribution, humoral immunity, cell-mediated immunity and splenic suppressor cell activity.
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The immunological disturbances occurring as a result of liver disease have been studied in an animal model of cirrhosis. The mononuclear phagocytic cells of the normal liver phagocytose large amounts of antigen irrespective of whether that antigen is injected directly into the portal or into the systemic circulations. The liver therefore acts as a filter 'in series' and 'in parallel' with the spleen and reduces the immunogenicity of antigens entering the organism by either of these routes. In rats with hepatic cirrhosis, there is a reduction in the capacity of the liver to phagocytose the flagellar antigen of Salmonella adelaide. This results in increased stimulation of splenic lymphoid tissue and in an increased antibody response to this thymus-independent antigen. The increased antigenic stimulus to the spleen may also be responsible for the increased suppressor-cell activity which has been demonstrated in these rats, and may be the mechanism of the diminished cell-mediated immune response both in this animal model of cirrhosis and in the human disease state. These studies suggest that many of the immunological disturbances associated with chronic liver disease may be the result of maldistribution of antigen occurring because of impaired hepatic phagocytic capacity. (+info)
Induction of corneal graft rejection by passive cell transfer.
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An experimental model is presented demonstrating that penetrating corneal grafts in the rabbit may be rejected by passive transfer into the anterior chamber of specifically sensitized lymphoid cells. Destruction of histo-incompatible corneal endothelium is always marked by the formation of focal pock-like areas of damage in this system, rather than by the typical moving line of rejecting endothelium usually seen in spontaneous graft rejection. Where the transferred lymphoid cells are compatible with the tissues of the graft recipient, the picture is one of a severely affected graft on a field of uninvolved recipient corneal endothelium. Where the lymphoid cells are compatible with the graft and not with the tissues of the recipient, one sees a clear corneal graft surviving on a field of endothelial destruction on the recipient bed. The specificity of these reactions is illustrated in terms of the histocompatibility relationships between corneal donor, graft recipient, and the donor of the sensitized lymphoid cells. (+info)
Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat.
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The present study was designed to determine whether .N = O produced in vivo during the rejection of histoincompatible tissues might permit serum NO2-/NO3- levels to serve as markers of a rejection reaction. Rat syngeneic and allogeneic liver, heart, bone marrow/spleen cell, small bowel, skin, and sponge matrix grafts were performed and the stable end-products of .N = O, NO2-/NO3-, were serially assayed in the serum of the grafted animals. A significant rise of serum NO2-/NO3- levels in the allografted animals preceded the onset of clinical signs of rejection or graft-versus-host disease, with the exception of the skin and sponge matrix graft models, where elevated serum NO2-/NO3- levels were never observed. In all transplant models, normal serum NO2-/NO3- levels were observed at all times in animals that received syngeneic grafts. Furthermore, treatment of allograft recipients with the immunosuppressive agents FK 506 or cyclosporine A inhibited .N = O production. Determination of serum creatinine levels demonstrated that the elevated serum NO2-/NO3- levels were not caused by kidney dysfunction. Serum NO2-/NO3- levels might be useful early serum markers of the initiation of a rejection reaction or graft-versus-host disease when functional markers of graft dysfunction are not apparent. (+info)