Prolongation of fully allogeneic skin graft survival in the rat by combined administration of costimulatory blockade and sirolimus.
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Animals↗
Biomedical subjects
R Peach
Publications and source records attributed to R Peach.
CD28-B7-mediated T cell costimulation in chronic cardiac allograft rejection: differential role of B7-1 in initiation versus progression of graft arteriosclerosis.
Provision of adequate T cell costimulation is critical for the development of acute and chronic allograft rejection. We have previously reported that early blockade of CD28-B7 T cell costimulation prevents the development of graft arteriosclerosis, in the LEW into F344 rat cardiac transplant model. In this study, we used the same model to examine the requirement for CD28-B7-mediated T cell costimulation in the progression of established chronic rejection and examined the individual roles of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules. Late blockade of CD28-B7 T cell costimulation by the fusion protein CTLA4Ig, which binds both CD80 and CD86, attenuated the development of transplant arteriosclerosis, mononuclear cell infiltration, and parenchymal fibrosis in this model. Selective blockade of CD80 using the mutant fusion protein Y100F was as effective as CTLA4Ig in this regard. In contrast to CTLA4Ig, blockade of CD80 alone by Y100F was ineffective at preventing early graft loss and prolonging graft survival when given early after transplantation. This study is the first to demonstrate that late blockade of CD28-B7 T cell costimulation interrupts chronic cardiac allograft rejection, and it indicates the importance of continued T cell activation in this process. This study further defines functional differences between CD80 and CD86 costimulatory molecules in vivo.
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On the existence of surface acoustic waves on piezoelectric substrates.
The existence of surface waves on anisotropic materials was proven under fairly general conditions by Lothe and Barnett in 1976 [1]. But, until now, the status of surface waves on piezoelectric materials has remained unresolved. This paper presents general existence theorems for surface waves on piezoelectric substrates. It is demonstrated that for short circuit boundary conditions a surface wave solution must exist under virtually any circumstances. However, for a free surface, comparatively stringent existence conditions are required. Numerical examples are given for both free and shorted surfaces, and it is demonstrated that, in some situations, a surface wave solution may not exist for free surface propagation. The existence proofs were developed as a result of theoretical work on Green function modeling, which is now the preferred technique for rigorous SAW and pseudo-SAW device analysis. The mechanisms of the existence proofs and the associated mathematical results give great insight into the structure and properties of the Green functions and include many results that are directly relevant to device analysis.
Journal Article↗
B7 requirements for primary and secondary protein- and polysaccharide-specific Ig isotype responses to Streptococcus pneumoniae.
The requirements for B7 costimulation during an in vivo humoral response to an intact extracellular bacteria have not been reported. In this study we immunized mice with Streptococcus pneumoniae (R36A) to determine the B7 requirements for induction of Ig, specific for two determinants on R36A, the phosphorylcholine (PC) determinant of C-polysaccharide and pneumococcal surface protein A (PspA). We show that the primary anti-PspA response, the development of PspA-specific memory, and the induction of the secondary anti-PspA response in primed mice were completely dependent upon B7 costimulation. Of note, costimulation was required only briefly after the secondary immunization compared with after the primary immunization for optimal induction of Ig. Blockade of B7 costimulation at the time of secondary immunization also completely abrogated the established state of memory, but did not induce tolerance. In contrast to the anti-PspA response, the primary anti-PC response involved only a very short period of B7 costimulation. Whereas B7-2 alone was required for induction of the primary anti-PspA and anti-PC responses, a redundant role for B7-1 and B7-2 was noted for the PspA-specific secondary response. CTLA4Ig blocked both the anti-PC and anti-PspA responses equally well over a wide range of bacterial doses. These studies demonstrate a critical, but variable, role for B7-dependent costimulation during an Ig response to an extracellular bacteria.
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IL-13-mediated worm expulsion is B7 independent and IFN-gamma sensitive.
B7 costimulation is a required component of many type 2 immune responses, including allergy and protective immunity to many nematode parasites. This response includes elevations in Th2 cytokines and associated effector functions including elevations in serum IgG1 and IgE and parasite expulsion. In studies of mice infected with Trichuris muris, blocking B7 ligand interactions inhibited protective immunity, suppressed IL-4 production, and enhanced IFN-gamma production, but unexpectedly did not inhibit production of the Th2 cytokine, IL-13. Blocking both IFN-gamma and B7 restored protective immunity, which was IL-13 dependent, but did not restore IL-4 or associated IgE responses. Although IL-13 was required for worm expulsion in mice in which both IFN-gamma and B7 were blocked, IL-4 could mediate expulsion in the absence of both IL-13 and IFN-gamma. These studies demonstrate that 1) B7 costimulation is required to induce IL-4, but not IL-13 responses; 2) IL-13 is elevated in association with the IFN-gamma response that occurs following inhibition of B7 interactions, but can only mediate IL-4-independent protection when IFN-gamma is also inhibited; and 3) increased IL-13 production, in the absence of increased IL-4 production, is not associated with an IgE response, even in the absence of IFN-gamma.
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Administration of CTLA4-Ig enhances the incidence of hamster-to-rat xenogeneic bone marrow engraftment and alters the presentation of graft-vs-host disease.
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Bacterial pathogens induce abscess formation by CD4(+) T-cell activation via the CD28-B7-2 costimulatory pathway.
Abscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naïve rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, including Staphylococcus aureus, Bacteroides fragilis, and a combination of Enterococcus faecium and Bacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28-B7-2 pathway.
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Blockade of costimulation prevents infection-induced immunopathology in interleukin-10-deficient mice.
Interleukin-10 (IL-10) is associated with inhibition of cell-mediated immunity and downregulation of the expression of costimulatory molecules required for T-cell activation. When IL-10-deficient (IL-10KO) mice are infected with Toxoplasma gondii, they succumb to a T-cell-mediated shock-like reaction characterized by the overproduction of IL-12 and gamma interferon (IFN-gamma) associated with widespread necrosis of the liver. Since costimulation is critical for T-cell activation, we investigated the role of the CD28-B7 and CD40-CD40 ligand (CD40L) interactions in this infection-induced immunopathology. Our studies show that infection of mice with T. gondii resulted in increased expression of B7 and CD40 that was similar in wild-type and IL-10KO mice. In vivo blockade of the CD28-B7 or CD40-CD40L interactions following infection of IL-10KO mice with T. gondii did not affect serum levels of IFN-gamma or IL-12, nor did it prevent death in these mice. However, when both pathways were blocked, the IL-10KO mice survived the acute phase of infection and had reduced serum levels of IFN-gamma and alanine transaminase as well as decreased expression of inducible nitric oxide synthase in the liver and spleen. Analysis of parasite-specific recall responses from infected IL-10KO mice revealed that blockade of the CD40-CD40L interaction had minimal effects on cytokine production, whereas blockade of the CD28-B7 interaction resulted in decreased production of IFN-gamma but not IL-12. Further reduction of IFN-gamma production was observed when both costimulatory pathways were blocked. Together, these results demonstrate that the CD28-B7 and CD40-CD40L interactions are involved in the development of infection-induced immunopathology in the absence of IL-10.
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CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis.
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The role of T cells in the pathogenesis of EAG remains unclear. T-cell costimulation is provided by ligation of CD28 with either B7.1 (CD80) or B7.2 (CD86) on antigen-presenting cells, and can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2. We examined the effect of CD28-B7 blockade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1. Native CTLA4-Ig treatment ameliorated EAG by several measures, including the levels of circulating anti-GBM antibodies, albuminuria, the deposition of IgG and fibrin in the glomeruli, the severity of glomerular abnormalities, and the numbers of infiltrating T cells and macrophages. Y100F-Ig resulted in a similar reduction in the severity of nephritis, but produced no overall reduction in circulating anti-GBM antibodies, although there was a reduction in IgG2a antibodies. We concluded that CD28-B7 blockade reduced autoantibody production and cellular infiltration of glomeruli, and prevented target organ injury. Our results suggest a key role for B7. 1 in costimulation of Th1-like autoimmune responses in the rat, and show that glomerular injury in EAG is largely dependent on cell-mediated mechanisms.
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Role of CD28 in the generation of effector and memory responses required for resistance to Toxoplasma gondii.
CD28 deficient (CD28-/-) mice were used to study the role of costimulation in the T cell-mediated, IFN-gamma-dependent mechanism of resistance to Toxoplasma gondii. These mice were resistant to infection with the ME49 strain of T. gondii. Analysis of the immune response of acutely infected CD28-/- mice revealed that IL-12 was required for T cell production of IFN-gamma and this was independent of the CD40/CD40 ligand interaction. A similar mechanism of IL-12-dependent, CD28/B7 independent production of IFN-gamma by T cells was also observed in wild-type mice. Interestingly, although chronically infected wild-type mice were resistant to rechallenge with the virulent RH strain of T. gondii, chronically infected CD28-/- mice were susceptible to rechallenge with the RH strain. This deficiency in the protective memory response by CD28-/- mice correlated with a lack of IL-2 and IFN-gamma in recall responses and reduced numbers of CD4+ T cells expressing a memory phenotype. Together, our findings demonstrate that CD28 is not required for the development of a protective T cell response to T. gondii, but CD28 is required for an optimal secondary immune response.
Animals↗
The CD28/B7 interaction is not required for resistance to Toxoplasma gondii in the brain but contributes to the development of immunopathology.
Infection of C57BL/6 mice with Toxoplasma gondii leads to chronic encephalitis characterized by infiltration into the brain of T cells that produce IFN-gamma and mediate resistance to the parasite. Our studies revealed that expression of B7.1 and B7.2 was up-regulated in brains of mice with toxoplasmic encephalitis (TE). Because CD28/B7-mediated costimulation is important for T cell activation, we assessed the contribution of this interaction to the production of IFN-gamma by T cells from brains and spleens of mice with TE. Stimulation of splenocytes with Toxoplasma Ag or anti-CD3 mAb resulted in production of IFN-gamma, which was inhibited by 90% in the presence of CTLA4-Ig, an antagonist of B7 stimulation. However, production of IFN-gamma by T cells from the brains of these mice was only slightly reduced (20%) by the addition of CTLA4-Ig. To address the role of the CD28/B7 interaction during TE, we compared the development of disease in C57BL/6 wild-type (wt) and CD28-/- mice. Although the parasite burden was similar in wt and CD28-/- mice, CD28-/- mice developed less severe encephalitis and survived longer than wt mice. Ex vivo recall responses revealed that mononuclear cells isolated from the brains of chronically infected CD28-/- mice produced less IFN-gamma than wt cells, and this correlated with reduced numbers of intracerebral CD4+ T cells in CD28-/- mice compared with wt mice. Taken together, our data show that resistance to T. gondii in the brain is independent of CD28 and suggest a role for CD28 in development of immune-mediated pathology during TE.
Animals↗
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.
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Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model.
Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that CD28-B7 blockade by systemic administration of CTLA4Ig prevents actively induced EAE. Since CTLA4Ig binds to both B7-1 and B7-2, we used a mutant form of CTLA4Ig (CTLA4IgY100F) that binds only B7-1, to study the role of B7-1 blockade in this model. Such a reagent avoids the potential of signaling by mAbs. Systemic administration of CTLA4IgY100F in several dosing regimens did not protect from EAE, and in some protocols worsened disease, while CTLA4Ig was always protective. In contrast, systemic injection of APCs preincubated ex vivo with the encephalitogenic peptide of myelin basic protein and either CTLA4Ig or CTLA4IgY100F protected recipients from disease. In vitro studies confirmed the in vivo observations and showed that primed lymph node cells from protected animals had decreased proliferative responses to myelin basic protein as compared with controls, while lymphocytes from animals treated with systemic CTLA4gY100F did not. More importantly, systemic administration of CTLA4IgY100F abrogated the protective effect of ex vivo treated APCs. These data suggest an important regulatory role for B7-1, perhaps through binding to CTLA4, in this model of EAE. Understanding the role and mechanisms of selective blockade of costimulatory molecules has implications for therapy of autoimmune disease.
Animals↗
CD28-B7 T cell costimulatory blockade by CTLA4Ig in sensitized rat recipients: induction of transplantation tolerance in association with depressed cell-mediated and humoral immune responses.
We tested the effects of blocking CD28-B7 T cell costimulation by using CTLA4Ig in an established transplantation model in which LBNF1 cardiac allografts are rejected in an accelerated manner (<36 h) by LEW rats presensitized with Brown-Norway skin grafts. Treatment with CTLA4Ig with or without donor alloantigen in the sensitization phase (between skin and cardiac engraftment) minimally delayed accelerated rejection. However, adjunctive infusion of CTLA4Ig and donor alloantigen in the effector phase (after cardiac engraftment) resulted in long term graft survival and donor-specific tolerance in 30 to 50% of the recipients. The mutant form of CTLA4Ig, which blocks B7-1 but not B7-2, was ineffective. The tolerant state was accompanied by reduction of cell-mediated (MLR/CTL) responses and depression of humoral (circulating IgM/IgG allo-Abs) alloreactivity in vivo. Hence, the binding of CD28 on T cells to both CD80 and CD86 ligands represents a crucial initial costimulatory step leading to accelerated graft rejection. CTLA4Ig-mediated early blockade of the CD28 signaling pathway combined with transfusion of donor cells in the perioperative period interrupts sensitization and may produce transplantation tolerance. This regimen inhibits T cell costimulation and activation to provide help to CD8+ cytotoxic T and B cells, perhaps, via CTLA4Ig-induced clonal anergy or deletion.
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The role of donor and recipient B7-1 (CD80) in allograft rejection.
Blockade of CD28-mediated T cell costimulatory signals produces effective immunosuppression of a variety of T cell-dependent in vivo immune responses, including autoimmune disorders and transplant rejection. The soluble fusion protein CTLA4Ig, which competitively blocks CD28 ligands B7-1 and B7-2, can prevent allograft and xenograft rejection and in some circumstances induce transplantation tolerance. To determine the relative roles of B7-1 and B7-2 in graft rejection, we have performed islet and cardiac allografts with normal and B7-1(-/-) mice in conjunction with selective blocking reagents. We found that the absence of B7-1 on donor or recipient tissues leads to a slight prolongation of islet allograft survival, but has minimal or no effect on cardiac allograft survival. Allograft function is further prolonged in the islet model when both donor and recipient lack B7-1, although cardiac allograft survival is not prolonged. In the cardiac model, treatment with CTLA4Ig induces long term survival in B7-1(-/-) recipients regardless of donor status. In contrast, anti-B7-2 mAb leads to indefinite allograft survival only when the recipient and donor both lack B7-1, indicating that even in the absence of available B7-2, B7-1 molecules on the donor or recipient cells alone are sufficient to induce graft rejection. These data also indicate that B7-1 and B7-2 are the only CD28 ligands relevant to cardiac allograft rejection in mice.
Animals↗
Effects of blocking B7-1 and B7-2 interactions during a type 2 in vivo immune response.
The costimulatory signal provided to T cells through CD28/CTLA-4 interactions is required for in vivo Th cell effector function associated with cytokine production. However, it is uncertain whether the two well-characterized ligands for these molecules, B7-1 and B7-2, differentially influence the consequent development of a type 1 or a type 2 primary response. We have examined the in vivo effects of blocking B7-1 and/or B7-2 ligand interactions on the type 2 mucosal immune response that follows oral infection of mice with the nematode parasite, Heligmosomoides polygyrus. Administration of the combination of anti-B7-1 and anti-B7-2 Abs inhibited H. polygyrus-induced increases in serum IgG1 and IgE levels, the expansion of mesenteric lymph node (MLN) germinal centers, in situ CD4+ T cell expansion, elevated blood eosinophils, and increased intestinal mucosal mast cells. Similarly, both Abs blocked MLN and Peyer's patch cytokine gene expression and elevations in MLN T cell-derived IL-4 protein secretion. However, in the same experiments, administration of either anti-B7-1 or anti-B7-2 Abs alone had little effect on any of these parameters. T cell and B cell activation was also blocked by the combination of anti-B7-2 and a B7-1-specific mutant Y100F CTLA-4Ig construct. These results suggest that to the extent that anti-B7-1 and anti-B7-2 mAbs block B7 interactions, either B7-1 or B7-2 ligand interactions can provide the required costimulatory signals that lead to T cell effector function during a type 2 in vivo immune response.
Animals↗
CD80 costimulation is essential for the induction of airway eosinophilia.
CD80 and CD86 (B7-1 and B7-2) are the ligands on antigen-presenting cells (APCs) which bind CD28 and deliver the costimulatory signals necessary for T cell activation. The reasons for the existence of two CD28 binding molecules are not well understood. We created a mutant version of CTLA4-Ig that could selectively bind CD80 and block CD28-CD80 interaction but leave CD28-CD86 binding intact. CD80 blockade prevented antigen-induced accumulation of eosinophils and lymphocytes in the lung of immunized mice, but did not block antigen induced systemic blood eosinophilia or IgE antibody production. No preferential expression of CD80 could be demonstrated on a population of lung APC consisting mainly of macrophages. These results indicate that CD80 costimulation is not necessary for the induction of Th2 immune responses but rather for the maintenance or amplification of lung inflammatory responses.
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CD28-b7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury.
Ischemic injury to cadaver organs is a major risk factor for development of chronic organ dysfunction. We have recently shown that the B7 costimulatory pathway plays a critical role in early organ dysfunction developing after renal cold ischemia/reperfusion injury. We extended these observations to investigate the role of this pathway in the development and progression of chronic organ dysfunction following such injury. Uninephrectomized rats which underwent cold ischemia/reperfusion injury developed progressive proteinuria as compared to uninephrectomized controls. Animals treated with CTLA4Ig, which blocks B7 costimulation, starting on the day of injury had significantly better long-term survival and developed significantly less proteinuria than control animals treated with control Ig. RT-PCR analysis of kidney tissue showed significant reduction in expression of activation and inflammatory cytokines, chemoattractants, and growth factors, as compared to controls. Delaying administration of CTLA4Ig for one week, but not four weeks, after injury was still effective in ameliorating development of progressive proteinuria. Interestingly, selective blockade of B7-1 by a mutant form of CTLA4Ig had no effect on early or chronic organ dysfunction. These findings indicate the long-term functional and molecular consequences of experimental cold ischemia/reperfusion injury, and suggest that B7-2 is critical in the development of organ dysfunction following ischemic injury, even in the absence of alloantigen.
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