Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation in... more Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation into microparticles. The cholesterol-lowering efficacy of nutraceutical combinations (NC) has not been investigated in patients with low-grade systemic inflammation and normal-borderline cholesterol levels. This is a 3-month prospective randomized open-label interventional study in patients with elevated plasma high sensitivity C-reactive protein (hsCRP) levels (>2 mg/L) and low-density lipoprotein (LDL) cholesterol of 100-160 mg/dL. The effect of either an oral cholesterol-lowering nutraceutical combination (NC) or no active treatment (noNC) was tested on LDL cholesterol, hsCRP and endothelial microparticle (EMPs) levels. Patients taking the NC had a significant reduction of total (-12%) and LDL cholesterol (-23%) compared to those who received noNC (p < 0.001 for both). Also, hsCRP and EMPs were significantly reduced by the NC (-41% and -16%, respectively). LDL cholesterol change was positively associated with hsCRP (rho = 0.21, p = 0.04) and EMP changes (rho = 0.56, p < 0.001), hsCRP and EMP changes being associated with each other (rho = 0.28, p = 0.005). Patients experiencing both LDL cholesterol and hsCRP reduction were those having the greatest EMP decrease. In conclusion, among patients with low-grade systemic inflammation, an oral NC significantly improved cholesterol profile and attenuated the degree of systemic inflammation and endothelial injury.
Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradatio... more Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-γ and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-γ and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-γ differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH. Wild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund's adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model. No differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells. Our data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.
To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotectiv... more To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.
We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (S... more We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].
Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such t... more Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small inte...
Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to t... more Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to the generation of immunogenic variant lines expressing new transplantation Ags recognized by CTL. In one such clonal variant (clone D), at least one subset of T cell neoepitopes are provided by proteins previously shown by serology to be products of endogenous retroviral env sequences. We report here on characterization of PCR-amplified gp70 env genes in clone D. Relative to known gp70 sequences in parental cells and in current databases, one gp70 sequence presented four distinct nucleotide changes, two of which were apparently unique to clone D DNA and cDNA upon differential hybridization analysis. Transfection experiments with the entire gp70 gene or subgenic fragments encompassing a single putative mutation showed that products of the mutated env gene or fragments may confer immunogenicity in vivo and susceptibility in vitro to lysis by clone D-primed, H-2Kd- or H-2Ld-restricted CTL. B...
Porcine Sertoli cells (pSCs) have been employed for cell therapy in pre-clinical studies for seve... more Porcine Sertoli cells (pSCs) have been employed for cell therapy in pre-clinical studies for several chronic/immune diseases as they deliver molecules associated with trophic and anti-inflammatory effects. To be employed for human xenografts, pSCs products need to comply with safety and stability. To fulfill such requirements, we employed a microencapsulation technology to increase pre-transplant storage stability of specific pathogen-free pSCs (SPF-pSCs) and evaluated the in vivo long-term viability and safety of grafts. Specific pathogen free neonatal pigs underwent testis excision under sterility. pSCs were isolated, characterized by immunofluorescence (IF) and cytofluorimetric analysis (CA) and examined in terms of viability and function [namely, production of anti-müllerian hormone (AMH), inhibin B, and transforming growth factor beta-1 (TFGβ-1)]. After microencapsulation in barium alginate microcapsules (Ba-MC), long-term SPF-pSCs (Ba-MCpSCs) viability and barium concentrations were evaluated at 1, 24 throughout 40 h to establish pre-transplant storage conditions. The purity of isolated pSCs was about 95% with negligible contaminating cells. Cultured pSCs monolayers, both prior to and after microencapsulation, maintained high function and full viability up to 24 h of storage. At 40 h post-encapsulation, pSCs viability decreased to 80%. Barium concentration in Ba-MCpSCs lagged below the normal maximum daily allowance and was stable for 4 months in mice with no evident side effects. Such results suggest that this protocol for the isolation and microencapsulation of pSCs is compatible with long-haul transportation and that Ba-MCpSCs could be potentially employable for xenotransplantation.
The idea of a possible involvement of the Aryl hydrocarbon Receptor (AhR) in transplant tolerance... more The idea of a possible involvement of the Aryl hydrocarbon Receptor (AhR) in transplant tolerance can be traced back to more than thirty years ago, when Clark and coworkers found that very low doses of dioxin, the most potent AhR ligand, markedly reduced the generation of cytotoxic T lymphocytes in response to alloantigen challenge in vivo. AhR is, indeed, a ligand-activated transcription factor that is activated by dioxins and other environmental pollutants. We now know that AhR can bind a broad variety of activating ligands, disparate in nature, including endogenous molecules and those formed in the gut from food and bacterial products. Therefore, in addition to its classical role as a toxicological signal mediator, AhR is emerging as a transcription factor involved in the regulation of both innate and adaptive immune responses in various immune cell types, including lymphocytes and antigen-presenting cells. Allograft rejection is mostly a T-cell-mediated alloimmune response, initiated by the recognition of alloantigens presented by donor and recipient antigen-presenting cells to recipient CD4(+) and CD8(+) T cells. Based on those findings, AhR may function as a critical sensor of the outside/inside environments, leading to changes in the immune system that may have relevance in transplantation. This article is protected by copyright. All rights reserved.
Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for... more Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immuno-suppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined Talpha1 for possible induction of DC-dependent regulatory effects. Talpha1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by Talpha1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, Talpha1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory enviro...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1996
Although transfection to express any of a multitude of immunomodulatory molecules can lead to the... more Although transfection to express any of a multitude of immunomodulatory molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the induction of tumor-specific CTL. Examination of the costimuli used by the host immune response during the normal rejection of immunogenic tumors should reveal critical cofactors for CTL differentiation in vivo. The involvement of a host B7 family costimulator molecule in the rejection of immunogenic tum- variants of the mastocytoma P815 was explored. Rejection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTLA4 ligand provided by the host in the rejection of B7- tumors. Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4+ cells, suggesting that CD8+ lymphocytes may receive direct costimulation by B7 in vivo. Fi...
Journal of immunology (Baltimore, Md. : 1950), 1995
Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to t... more Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to the generation of immunogenic variant lines expressing new transplantation Ags recognized by CTL. In one such clonal variant (clone D), at least one subset of T cell neoepitopes are provided by proteins previously shown by serology to be products of endogenous retroviral env sequences. We report here on characterization of PCR-amplified gp70 env genes in clone D. Relative to known gp70 sequences in parental cells and in current databases, one gp70 sequence presented four distinct nucleotide changes, two of which were apparently unique to clone D DNA and cDNA upon differential hybridization analysis. Transfection experiments with the entire gp70 gene or subgenic fragments encompassing a single putative mutation showed that products of the mutated env gene or fragments may confer immunogenicity in vivo and susceptibility in vitro to lysis by clone D-primed, H-2Kd- or H-2Ld-restricted CTL. B...
Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation in... more Cholesterol elevations are associated with systemic inflammation and endothelial fragmentation into microparticles. The cholesterol-lowering efficacy of nutraceutical combinations (NC) has not been investigated in patients with low-grade systemic inflammation and normal-borderline cholesterol levels. This is a 3-month prospective randomized open-label interventional study in patients with elevated plasma high sensitivity C-reactive protein (hsCRP) levels (>2 mg/L) and low-density lipoprotein (LDL) cholesterol of 100-160 mg/dL. The effect of either an oral cholesterol-lowering nutraceutical combination (NC) or no active treatment (noNC) was tested on LDL cholesterol, hsCRP and endothelial microparticle (EMPs) levels. Patients taking the NC had a significant reduction of total (-12%) and LDL cholesterol (-23%) compared to those who received noNC (p < 0.001 for both). Also, hsCRP and EMPs were significantly reduced by the NC (-41% and -16%, respectively). LDL cholesterol change was positively associated with hsCRP (rho = 0.21, p = 0.04) and EMP changes (rho = 0.56, p < 0.001), hsCRP and EMP changes being associated with each other (rho = 0.28, p = 0.005). Patients experiencing both LDL cholesterol and hsCRP reduction were those having the greatest EMP decrease. In conclusion, among patients with low-grade systemic inflammation, an oral NC significantly improved cholesterol profile and attenuated the degree of systemic inflammation and endothelial injury.
Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradatio... more Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-γ and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-γ and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-γ differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH. Wild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund's adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model. No differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells. Our data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.
To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotectiv... more To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.
We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (S... more We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].
Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such t... more Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small inte...
Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to t... more Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to the generation of immunogenic variant lines expressing new transplantation Ags recognized by CTL. In one such clonal variant (clone D), at least one subset of T cell neoepitopes are provided by proteins previously shown by serology to be products of endogenous retroviral env sequences. We report here on characterization of PCR-amplified gp70 env genes in clone D. Relative to known gp70 sequences in parental cells and in current databases, one gp70 sequence presented four distinct nucleotide changes, two of which were apparently unique to clone D DNA and cDNA upon differential hybridization analysis. Transfection experiments with the entire gp70 gene or subgenic fragments encompassing a single putative mutation showed that products of the mutated env gene or fragments may confer immunogenicity in vivo and susceptibility in vitro to lysis by clone D-primed, H-2Kd- or H-2Ld-restricted CTL. B...
Porcine Sertoli cells (pSCs) have been employed for cell therapy in pre-clinical studies for seve... more Porcine Sertoli cells (pSCs) have been employed for cell therapy in pre-clinical studies for several chronic/immune diseases as they deliver molecules associated with trophic and anti-inflammatory effects. To be employed for human xenografts, pSCs products need to comply with safety and stability. To fulfill such requirements, we employed a microencapsulation technology to increase pre-transplant storage stability of specific pathogen-free pSCs (SPF-pSCs) and evaluated the in vivo long-term viability and safety of grafts. Specific pathogen free neonatal pigs underwent testis excision under sterility. pSCs were isolated, characterized by immunofluorescence (IF) and cytofluorimetric analysis (CA) and examined in terms of viability and function [namely, production of anti-müllerian hormone (AMH), inhibin B, and transforming growth factor beta-1 (TFGβ-1)]. After microencapsulation in barium alginate microcapsules (Ba-MC), long-term SPF-pSCs (Ba-MCpSCs) viability and barium concentrations were evaluated at 1, 24 throughout 40 h to establish pre-transplant storage conditions. The purity of isolated pSCs was about 95% with negligible contaminating cells. Cultured pSCs monolayers, both prior to and after microencapsulation, maintained high function and full viability up to 24 h of storage. At 40 h post-encapsulation, pSCs viability decreased to 80%. Barium concentration in Ba-MCpSCs lagged below the normal maximum daily allowance and was stable for 4 months in mice with no evident side effects. Such results suggest that this protocol for the isolation and microencapsulation of pSCs is compatible with long-haul transportation and that Ba-MCpSCs could be potentially employable for xenotransplantation.
The idea of a possible involvement of the Aryl hydrocarbon Receptor (AhR) in transplant tolerance... more The idea of a possible involvement of the Aryl hydrocarbon Receptor (AhR) in transplant tolerance can be traced back to more than thirty years ago, when Clark and coworkers found that very low doses of dioxin, the most potent AhR ligand, markedly reduced the generation of cytotoxic T lymphocytes in response to alloantigen challenge in vivo. AhR is, indeed, a ligand-activated transcription factor that is activated by dioxins and other environmental pollutants. We now know that AhR can bind a broad variety of activating ligands, disparate in nature, including endogenous molecules and those formed in the gut from food and bacterial products. Therefore, in addition to its classical role as a toxicological signal mediator, AhR is emerging as a transcription factor involved in the regulation of both innate and adaptive immune responses in various immune cell types, including lymphocytes and antigen-presenting cells. Allograft rejection is mostly a T-cell-mediated alloimmune response, initiated by the recognition of alloantigens presented by donor and recipient antigen-presenting cells to recipient CD4(+) and CD8(+) T cells. Based on those findings, AhR may function as a critical sensor of the outside/inside environments, leading to changes in the immune system that may have relevance in transplantation. This article is protected by copyright. All rights reserved.
Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for... more Thymosin alpha1 (Talpha1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immuno-suppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined Talpha1 for possible induction of DC-dependent regulatory effects. Talpha1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by Talpha1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, Talpha1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory enviro...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1996
Although transfection to express any of a multitude of immunomodulatory molecules can lead to the... more Although transfection to express any of a multitude of immunomodulatory molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the induction of tumor-specific CTL. Examination of the costimuli used by the host immune response during the normal rejection of immunogenic tumors should reveal critical cofactors for CTL differentiation in vivo. The involvement of a host B7 family costimulator molecule in the rejection of immunogenic tum- variants of the mastocytoma P815 was explored. Rejection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTLA4 ligand provided by the host in the rejection of B7- tumors. Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4+ cells, suggesting that CD8+ lymphocytes may receive direct costimulation by B7 in vivo. Fi...
Journal of immunology (Baltimore, Md. : 1950), 1995
Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to t... more Exposure in vivo of murine L5178Y lymphoma cells to cytoreductive triazene derivatives leads to the generation of immunogenic variant lines expressing new transplantation Ags recognized by CTL. In one such clonal variant (clone D), at least one subset of T cell neoepitopes are provided by proteins previously shown by serology to be products of endogenous retroviral env sequences. We report here on characterization of PCR-amplified gp70 env genes in clone D. Relative to known gp70 sequences in parental cells and in current databases, one gp70 sequence presented four distinct nucleotide changes, two of which were apparently unique to clone D DNA and cDNA upon differential hybridization analysis. Transfection experiments with the entire gp70 gene or subgenic fragments encompassing a single putative mutation showed that products of the mutated env gene or fragments may confer immunogenicity in vivo and susceptibility in vitro to lysis by clone D-primed, H-2Kd- or H-2Ld-restricted CTL. B...
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