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C P Genain

Publications and source records attributed to C P Genain.

29 records · Page 2Linked to original sources
PubMed1996

Late complications of immune deviation therapy in a nonhuman primate.

The administration of antigens in soluble form can induce antigen-specific immune tolerance and suppress experimental autoimmune diseases. In a marmoset model of multiple sclerosis induced by myelin oligodendrocyte glycoprotein (MOG), marmosets tolerized to MOG were protected against acute disease, but after tolerization treatment a lethal demyelinating disorder emerged. In these animals, MOG-specific T cell proliferative responses were transiently suppressed, cytokine production was shifted from a T helper type 1 (TH1) to a TH2 pattern, and titers of autoantibodies to MOG were enhanced. Thus, immune deviation can increase concentrations of pathogenic autoantibodies and in some circumstances exacerbate autoimmune disease.

Animals↗
PubMed1995

Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: a new model for multiple sclerosis.

A chronic relapsing-remitting form of experimental autoimmune encephalomyelitis was induced in the common marmoset Callithrix jacchus following a single immunization with human white matter. Individual animals in this species are born as natural bone marrow chimeras, allowing transfer of functional T-cell populations between genetically distinct siblings. The acute disease was characterized clinically by mild neurological signs. Pathologically, the disease was characterized by perivascular mononuclear cell infiltrates, large foci of primary demyelination, and reactive astrogliosis. No animal displayed hemorrhagic-necrotic lesions or polymorphonuclear cell infiltrates characteristic of other acute forms of primate experimental autoimmune encephalomyelitis. A late spontaneous relapse occurred in each of 2 animals followed for 3 to 12 months subsequent to recovery from the acute attack. In these animals, chronic lesions consisted of mononuclear cell infiltrates within large sharply defined areas of demyelination and astrogliosis, and resembled active plaques of chronic multiple sclerosis. Proliferative responses to myelin basic protein but not to myelin proteolipid protein were present in peripheral blood lymphocytes of immunized animals. Furthermore, myelin basic protein-reactive T-cell lines derived from immunized donors induced clinical signs of experimental autoimmune encephalomyelitis when adoptively transferred into a sibling, indicating that myelin basic protein-reactive T cells can induce disease in this species. Because of its clinical and pathological similarity to human multiple sclerosis and the ability to adoptively transfer experimental autoimmune encephalomyelitis, this model system should prove useful in the analysis of the immunological mechanisms responsible for autoimmune demyelination in outbred primates.

Animals↗
PubMed1995

Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate.

In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.

Animals↗
PubMed1994

In healthy primates, circulating autoreactive T cells mediate autoimmune disease.

A T cell response against myelin basic protein (MBP) is thought to contribute to the central nervous system (CNS) inflammation that occurs in the human demyelinating disease multiple sclerosis. To test whether MBP-reactive T cells that are normally retrieved from the circulation are capable of inducing CNS disease, MBP-reactive T cell clones were isolated from the peripheral blood of healthy, unimmunized Callithrix jacchus (C. jacchus) marmosets. This primate species is characterized by a natural chimerism of bone marrow elements between siblings that should make possible adoptive transfer of MBP-reactive T cells. We report that MBP-reactive T cell clones efficiently and reproducibly transfer CNS inflammatory disease between members of C. jacchus chimeric sets. The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones. It was noteworthy that encephalitogenic T cell clones were diverse in terms of their recognition of different epitopes of MBP, distinguishing the response in C. jacchus from that in some inbred rodents in which restricted recognition of MBP occurs. These findings are the first direct evidence that natural populations of circulating T cells directed against a CNS antigen can mediate an inflammatory autoimmune disease.

Animals↗
PubMed1990

Separation of brain dolichol kinase from endogenous activating factors: evidence that phospholipid enhances the interaction between enzyme and dolichol.

Porcine brain dolichol kinase activity is effectively solubilized by extracting salt-washed microsomes with 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). When the detergent-solubilized activity is chromatographed on Sepharose CL-6B, a low amount of dolichol kinase activity is recovered in the void volume, and a dolichol kinase activator (DKA) is eluted (Ve/Vo = 1.9-2.2) with the bulk of the membrane phospholipids. Although only approximately 20% of the activity applied to the Sepharose CL-6B column is detected in the column fractions, virtually all of the original activity is restored when the Vo fraction is recombined with DKA. Endogenous DKA, isolated from brain microsomes, is heat-stable, is extractable with CHCl3/CH3OH (2:1), and has the chemical and chromatographic properties of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Moreover, approximately 50% of the stimulatory activity is lost when the PC present in the DKA fraction is degraded by purified phospholipase C from Clostridium perfringens. Also consistent with a phospholipid co-factor requirement, the dolichol kinase activity recovered in the partially phospholipid-depleted fraction (Vo) is markedly stimulated by various molecular species of exogenous purified PC or PE, but not by phosphatidylinositol, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, or sphingomyelin. A comparison of defined molecular species shows that PCs containing oleoyl or linoleoyl groups in the 1 and 2 positions are the most stimulatory, suggesting that the fatty acyl moieties are involved in the enzyme-phospholipid interaction. Kinetic analyses indicate that PC enhances the interaction between dolichol kinase and dolichol, the lipophilic substrate, but does not alter the apparent Km for CTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Failure of salt loading to inhibit tissue norepinephrine turnover in prehypertensive Dahl salt-sensitive rats.

To determine if alterations of electrolyte balance or sympathetic nervous system activity are present in Dahl salt-sensitive rats (DS) before the onset of hypertension, we compared electrolyte balances, extracellular fluid volume (inulin space), plasma volume (radiolabeled albumin), and norepinephrine turnover in peripheral tissues (heart and interscapular brown fat) in prehypertensive DS and Dahl salt-resistant rats (DR). Animals were maintained for 5 to 7 days on either a "normal" or high NaCl diet. Tissue norepinephrine turnover was evaluated by measuring the rate at which norepinephrine content decreased following tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine. Blood pressure was higher (p less than 0.05) in DS (135 +/- 2 [SE] mm Hg) than in DR (129 +/- 2 mm Hg) and was not affected by the diets. Extracellular fluid volume and net Na+ and Cl- balances did not differ between DS and DR. However, plasma volume was greater in DS than in DR (p less than 0.05). In both fat and heart, norepinephrine turnover was decreased by dietary NaCl loading in DR (p less than 0.01), but not in DS. Thus, the tendency of the DS to become hypertensive with high NaCl intake may be related to the combined effects of an increased plasma volume and the failure of high dietary NaCl to inhibit peripheral sympathetic nervous system activity.

Animals↗
PubMed1985

Distribution of renin activity and angiotensinogen in rat brain. Effects of dietary sodium chloride intake on brain renin.

The purpose of this study was to investigate the biochemistry and the regulation of the brain renin-angiotensin system in the Sprague-Dawley rat. Renin activity and angiotensinogen concentrations (direct and indirect radioimmunoassays) were measured in several brain areas and in neuroendocrine glands. Regional renin activities were measured in separate groups of rats on high and low NaCl diets. Mean tissue renin activities ranged from 2.2 +/- 0.6 to 54.4 +/- 19.7 fmol/mg protein per h (mean of 7 +/- SD), with the highest amounts in pineal, pituitary, and pons-medulla. NaCl depletion increased renin activity in selected regions; based on estimates of residual plasma contamination (despite perfusion of brains with saline), increased renin activity of pineal gland and posterior pituitary was attributed to higher plasma renin. To eliminate contamination by plasma renin, 16-h-nephrectomized rats were also studied. In anephric rats, NaCl depletion increased renin activity by 92% in olfactory bulbs and by 97% in anterior pituitary compared with NaCl-replete state. These elevations could not be accounted for by hyperreninemia. Brain renin activity was low and was unaffected by dietary NaCl in amygdala, hypothalamus, striatum, frontal cortex, and cerebellum. In contrast to renin, highest angiotensinogen concentrations were measured in hypothalamus and cerebellum. Overall, angiotensinogen measurements with the direct and the indirect assays were highly correlated (n = 56, r = 0.96, P less than 0.001). We conclude that (a) NaCl deprivation increases renin in olfactory bulbs and anterior pituitary of the rat, unrelated to contamination by plasma renin; and (b) the existence of angiotensinogen, the precursor of angiotensins, is demonstrated by direct radioimmunoassay throughout the brain and in neuroendocrine glands.

Angiotensinogen↗
PubMed1982

Aortic input impedance in normal man and arterial hypertension: its modification during changes in aortic pressure.

The purpose of this work was to study the factors determining aortic input impedance in hypertensive patients. Aortic input impedance (simultaneous measurements of aortic pressure and blood flow), mean (Wm) and pulsatile (Wp) powers and the Wp/Wm ratio were compared in normal subjects (n = 13) and hypertensive patients (n = 12) under basal conditions and during blood pressure manipulation--angiotensin infusion in five normal patients and nitroprusside infusion in six hypertensive patients. Pulse wave velocity (Möens-Korteweg equation; simultaneous measurement of aortic pressure and radius) was determined under basal conditions in normal subjects and in 11 hypertensive patients. The results show that: 1) the changes in impedance curves in hypertensive patients are related to increased peripheral resistance, pulse wave velocity, wave reflection and aortic radius; 2) in most hypertensive patients impedance curves are normalised when blood pressure is reduced, whereas the Wp/Wm ratio remains higher. This latter result demonstrates that pulsatile energy losses are greater in hypertensive patients and suggests either that the aortic wall remains stiffer, despite the reduction in aortic pressure, or that the flow wave becomes more pulsatile since impedance curves of hypertensive patients seen after lowering blood pressure are similar to those of normal subjects.

Adult↗
PubMedDate not supplied

Cloning, sequencing, and homology analysis of nonhuman primate Fas/Fas-ligand and co-stimulatory molecules.

The finding that a single administration of select recombinant human cytokines to nonhuman primates leads to potent cytokine-neutralizing antibody responses in the heterologous host despite >95% homology at the nucleotide and protein level prompted our laboratory to clone, sequence, and prepare recombinant nonhuman primate cytokines, chemokines, growth factors, and other immunoregulatory molecules. In the present report, we present findings on the gene sequences encoding the nonhuman primate homologues of human CD80, CD86, their ligands CD28 and CD152, CD154, CD95, and CD95-L from rhesus macaques and for phylogenetic analysis from pig-tailed macaques, African sooty mangabey monkeys, baboons, and vervets as well as select molecules from the New World aotus and marmoset monkeys. With the exception of CD95, the homology between nonhuman primate and human co-stimulatory molecules was above 95%. In contrast, CD95 was only 89.2% homologous to human CD95, but the differences were essentially found in the transmembrane and intracellular (death) domains. The extracellular portion of CD95 was more homologous which was in accordance with approximately 98% homology between Old World monkey and human CD95-L. In general, sequences from the New World monkey species appeared equidistant to sequences from Old World species and humans in terms of homology suggesting distinct evolutionary patterns. Of interest was the isolation of various splice variants of monkey CD86, CD152 (CTLA-4), CD154, and CD95 transcripts. This is also the first report documenting the occurrence of natural CD86 variants with deleted transmembrane domains, found both in sooty mangabeys and baboon RNA samples. Monkey CD95 showed various deletions and addition of residues in the transmembrane and intracytoplasmic domains compared with human CD95 and between Old and New World species. Subcloning of rhesus CD154 into an expression vector demonstrated expression of a functional protein in cell culture. The other genes are being cloned into expression vectors for the preparation and biological characterization of the nonhuman primate molecules. These investigations will provide novel reagents for in vivo use as immunomodulatory reagents in nonhuman primates in studies which may provide a rationale for their use in humans.

Abatacept↗