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Biomedical subjects

M H Sayegh

Publications and source records attributed to M H Sayegh.

At least 55 records · Page 3Linked to original sources
PubMed1999

Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2.

BACKGROUND: CD4-targeted therapy or blocking of CD28-B7 T-cell costimulation may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways after the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig). METHODS AND RESULTS: Lewis rats sensitized with Brown Norway skin grafts reject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 monotherapy uniformly produced permanent cardiac graft acceptance, whereas CTLA4Ig produced indefinite graft survival in about 50% of sensitized rats. Spleen cells (100 x 10(6)) from CD4 mAb-treated rats conferred donor-specific tolerance after transfer into new sets of recipients. This tolerant state could be then transferred with regulatory cells in an infectious manner into new cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300 x 10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviving grafts in both groups were largely protected from signs of chronic rejection. CONCLUSIONS: CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-mediated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance and attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not required for tolerance maintenance, and it does not necessarily lead to chronic injury.

Abatacept↗
PubMed1999

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

INTRODUCTION: To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. METHODS: Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. RESULTS: Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. CONCLUSION: These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Animals↗
PubMed1999

Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis.

Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to block B7) after immunization or after the first attack protects from EAE. Treatment with a combination of CTLA4Ig and MR1 provides additive protection, and is associated with complete absence of mononuclear cell infiltrates in the central nervous system, and marked suppression of proliferation of primed T cells in the periphery. Selective B7-1 blockade did not protect from EAE. These observations have implications for therapy of autoimmune diseases.

Abatacept↗
PubMed1999

CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment.

Sensitization to donor Ags is an enormous problem in clinical transplantation. In an islet allograft model, presensitization of recipients through donor-specific transfusion (DST) 4 wk before transplantation results in accelerated rejection. We demonstrate that combined DST with anti-CD154 (CD40L) therapy not only prevents the deleterious presensitization produced by pretransplant DST in the islet allograft model, it also induces broad alloantigen-specific tolerance and permits subsequent engraftment of donor islet or cardiac grafts without further treatment. In addition, our data strongly indicate that CTLA4-negative T cell signals are required to achieve prolonged engraftment of skin allograft or tolerance to islet allograft in recipients treated with a combination of pretransplant DST and anti-CD154 mAb. We provide direct evidence that a CD28-independent CTLA4 signal delivers a strong negative signal to CD4+ T cells that can block alloimmune MLR responses. In this study immune deviation into a Th2 (IL-4) response was associated with, but did not insure, graft tolerance, as the inopportune timing of B7 blockade with CTLA4/Ig therapy prevented uniform tolerance but did not prevent Th2-type immune deviation. While CTLA4-negative signals are necessary for tolerance induction, Th1 to Th2 immune deviation cannot be sufficient for tolerance induction. Combined pretransplant DST with anti-CD154 mAb treatment may be attractive for clinical deployment, and strategies aimed to selectively block CD28 without interrupting CTLA4/B7 interaction might prove highly effective in the induction of tolerance.

Abatacept↗
PubMed1999

Immunomodulatory functions of hyaluronate in the LEW-to-F344 model of chronic cardiac allograft rejection.

BACKGROUND: CD44 is an important leukocyte cell surface glycoprotein with diverse functions including cell adhesion, homing, migration, and activation. METHODS: Because administration of the principal ligand of CD44, hyaluronate (HA), in soluble form, can inhibit CD44-HA interaction, we tested the effects of HA in vivo in an established model of chronic allograft rejection. Control F344 recipients of LEW hearts received either no treatment or low-dose cyclosporine (CsA) for 30 days from the day of transplantation. Experimental animals received 30 days of CsA in combination with 30 or 90 days of low molecular weight HA (LMW-HA). RESULTS: CsA therapy alone resulted in approximately 40% long-term (>100 days) graft survival, whereas CsA + LMW-HA (30-day and 90-day protocols) significantly increased long-term graft survival to 60% and 92%, respectively. Light microscopy and immunohistology of CsA-treated and CsA + LMW-HA-treated grafts harvested at day 30 after transplantation demonstrated that LMW-HA + CsA therapy decreased mononuclear cell infiltration and afforded better preservation of myocardial architecture. In addition, LMW-HA + CsA-treated grafts exhibited decreased expression of interferon-gamma and the growth factors transforming growth factor-beta, platelet-derived growth factor, and fibrogenic growth factor-beta. Long-term surviving grafts were assessed for arteriosclerosis, the sine qua non of chronic rejection in this model. Using a standardized scoring system, significantly less arteriosclerosis was seen in grafts from LMW-HA + CsA-treated animals at 120 days after transplantation compared with CsA alone-treated grafts. This difference was not significant, however, in grafts harvested at >150 days. CONCLUSION: This is the first report indicating that CD44-HA interactions play an important role in chronic allograft rejection.

Animals↗
PubMed1999

The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival.

Blocking the interaction of the CD28 costimulatory receptor with its ligands, CD80 and CD86, inhibits in vivo immune responses, such as allograft rejection, and in some instances induces tolerance. Previously, we found that CTLA4Ig, which blocks the CD28/CTLA-4 (CD152) ligands CD80 and CD86, can be used to induce transplantation tolerance to vascularized allografts. Recent data suggest that an intact CD152-negative signaling pathway is essential for induction of tolerance to nominal Ags. Here, we show that blockade of CD152 using an anti-CD152 mAb at the time of transplantation prevents the induction of long-term allograft survival by agents that target CD80 and CD86. In contrast, CD152 signals are not required for the maintenance of established graft survival. We also report for the first time that blockade of CD86 alone can induce long-term graft survival. This requires that anti-CD86 mAb is given on the day of transplantation and also depends upon an intact CD152 pathway. This result, plus experiments using CD80-deficient mice, suggests a dominant role for CD80 molecules on donor cells as the relevant ligand for CD152. We additionally find that blockade of CD152 at the time of transplantation does not interfere with the effectiveness of anti-CD154 mAbs, suggesting distinct mechanisms for inhibition of graft rejection by blocking the CD28 vs CD154 pathways.

Abatacept↗
PubMed1999

Acquired thymic tolerance: role of CTLA4 in the initiation and maintenance of tolerance in a clinically relevant autoimmune disease model.

Injection of Ag into the thymus of adult animals induces specific systemic tolerance. The mechanisms of acquired thymic tolerance include anergy and the deletion of Ag-specific T cells. Here, we report that anergy to nominal Ag induced via acquired thymic tolerance requires CTL-associated Ag 4 (CTLA4) engagement. The role of CTLA4 in the induction and maintenance of tolerance was then investigated in the murine experimental autoimmune encephalomyelitis model. CTLA4 blockade abrogated the induction but not the maintenance phase of acquired thymic tolerance induced by intrathymic injection of myelin Ags. In addition, CTLA4 blockade had a restricted window of action after priming with Ag, which is consistent with the expression patterns of CTLA4 in vivo. We conclude that: 1) the induction of acquired thymic tolerance requires signaling through CTLA4 and 2) CTLA4 does not appear to be required for the maintenance of acquired thymic tolerance. This is the first report documenting the role of a CTLA4 negative signaling pathway in the induction of tolerance in an autoimmune disease model.

Abatacept↗
PubMed1999

Transplantation tolerance: the concept and its applicability.

Recent advances have enabled researchers to induce tolerance in animal transplant models. Although it has been relatively easy to do so in rodents, it has been much more difficult to translate such strategies into primates. Understanding the cellular and molecular mechanisms of the alloimmune response has prompted the development of novel strategies that may obviate the need for immunosuppression in humans. Mechanisms of tolerance and promising new therapies, as well as the inherent difficulties in bringing them into clinical practice, are reviewed.

Animals↗
PubMed1999

The role of B/T costimulatory signals in the immunopotentiating activity of neisserial porin.

A T cell-dependent immune response to group C meningococcal capsular polysaccharide (CPS) can be elicited when CPS is conjugated to the class 3 neisserial porin (CPS-porin). Treatment of CPS-porin-immunized mice with B7-2 blocking monoclonal antibody (MAb) caused a dramatic reduction in the CPS-specific IgG response, treatment with anti-B7-1 MAb had no effect, and concurrent blockade of B7-1 and B7-2 resulted in a synergistic abrogation of the CPS-specific IgG response while the CPS IgM response was unaffected. Anti-CD40L MAb treatment caused a significant reduction of both CPS-specific IgG and IgM levels. In contrast, blockade of CTLA4 interactions resulted in increases in both CPS IgG and IgM responses in CPS-porin-immunized mice. These data support the hypothesis that the ability of neisserial porins to improve the immune response to poorly immunogenic antigens (e.g., polysaccharides) is related to porin-induced increases in B7-2 expression on antigen-presenting cells and enhanced B/T cell interactions.

Abatacept↗
PubMed1999

Cognate stimulatory B-cell-T-cell interactions are critical for T-cell help recruited by glycoconjugate vaccines.

Covalent linkage of a bacterial polysaccharide to an immunogenic protein greatly enhances the carbohydrate's immunogenicity and induces polysaccharide-specific B-cell memory in vivo. These findings have spurred the development of glycoconjugate vaccines for serious bacterial infections. The specific B-cell-T-cell interactions responsible for recruitment of T-cell help by glycoconjugate vaccines are not well defined. We used mice deficient in molecules critical for stimulatory, cognate B-cell-T-cell interactions to study how T cells improve the immunogenicity of a glycoconjugate vaccine against group B streptococcal disease. Isotype switching to immunoglobulin G (IgG) was abrogated in mice deficient in major histocompatibility complex (MHC) class II antigen (Ag)-T-cell receptor (TCR), B7-CD28, or CD40-CD40L interactions. However, expression of either the B7-1 or the B7-2 molecule on antigen-presenting cells was sufficient for optimal T-cell costimulation. T cells activated by the vaccine also played a pivotal role in determining the magnitude of the IgM response to the polysaccharide. Comparable results were obtained with pathway antagonists. These data suggest that MHC class II Ag-TCR, B7-CD28, and CD40-CD40L interactions are critical for immune responses to glycoconjugate vaccines in vivo.

Animals↗
PubMed1999

Inhibition of allorecognition by a human class II MHC-derived peptide through the induction of apoptosis.

The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.

Adjuvants, Immunologic↗
PubMed1999

Immunomodulatory functions of low-molecular weight hyaluronate in an acute rat renal allograft rejection model.

Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lymphocyte CD44 and hyaluronate (HA), a heteropolysaccharide that is expressed on the surface of endothelial cells and ubiquitously in the extracellular matrix. This study was undertaken to assess the ability of LMW-HA to modify the course of experimental acute renal allograft rejection. Lewis (LEW) rats were bilaterally nephrectomized and received an orthotopic, fully MHC-mismatched, Wistar-Furth (WF) kidney transplant. Animals received either no treatment, low doses of cyclosporin A (CsA) on days 0 to 5, LMW-HA on days 0 to 5, or CsA plus LMW-HA on days 0 to 5 after transplantation. With no treatment, CsA monotherapy, or HA monotherapy, animals rejected their allografts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, combined CsA plus LMW-HA therapy prevented acute rejection and significantly prolonged graft survival (P = 0.008) to a median of 49.0 d. CsA/LMW-HA-treated grafts also demonstrated better preservation of renal function at day 30 (serum creatinine level, 1.38+/-0.8 mg/dl), compared with surviving animals treated with CsA alone (2.9+/-0.55 mg/dl, P<0.05). Histologic graft analysis of CsA/LMW-HA-treated animals at day 7 after transplantation showed minimal rejection and leukocyte infiltration, compared with all other groups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, and interferon-gamma transcript levels in the combined-treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA in vivo in the setting of organ transplantation. Defining the exact mechanisms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation.

Adjuvants, Immunologic↗
PubMed1999

Blocking costimulatory signals to induce transplantation tolerance and prevent autoimmune disease.

Similar cellular and molecular mechanisms are responsible for the pathogenesis of transplant rejection and autoimmunity. Recent advances in the studies of lymphocyte activation have shown a requirement for two distinct signals for full activation and development of effector function. The first signal is antigen itself; the second is a nonspecific costimulatory signal, the best example of which is delivered through the CD28 receptor. We and others have shown that blockade of this costimulatory signal can be used as part of strategy to prevent or treat transplant rejection and autoimmune disorders in animal models. This paper will review these findings and discuss their implications for clinical use.

Abatacept↗
PubMed1999

Nocardial infection in a renal transplant recipient on tacrolimus and mycophenolate mofetil.

Infection with Nocardia spp. is an uncommon but important cause of morbidity and mortality in organ transplant recipients. Cotrimoxazole prophylaxis against urinary tract infection and Pneumocystis carinii pneumonia in these patients usually prevents nocardial infection also. We report the case of a patient on tacrolimus and mycophenolate mofetil who developed drug-induced diabetes mellitus followed by nocardial brain infection. This infection occurred despite conventional cotrimoxazole prophylaxis. Physicians should be aware that newer, more potent and more diabetogenic immunosuppressive regimens may increase the risk of opportunistic infections such as nocardiosis, even in the presence of "adequate" antimicrobial preventive measures.

Adult↗