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Biomedical subjects

C C Whitacre

Publications and source records attributed to C C Whitacre.

At least 55 records · Page 3Linked to original sources
PubMed1991

Facilitation of dimethylbenz[a]anthracene-induced rat mammary tumorigenesis by restraint stress: role of beta-endorphin, prolactin and naltrexone.

In order to investigate the involvement of opioid peptides and prolactin in stress-facilitated mammary cancer, we studied the effect of chronic restraint stress on dimethylbenz[a]-anthracene (DMBA)-induced mammary tumorigenesis and the effect of an opiate antagonist, naltrexone, on this process. Female Fischer-344 rats (n = 160) were administered 15 mg DMBA/ml of sesame oil/rat by intragastric intubation. Eighty rats were subjected to daily 30 min restraint stress in a plastic cylinder, and 80 rats served as control not subjected to the stressor. Half of the rats from each group received naltrexone (1 mg/kg, i.p. daily). Five rats from each group (restraint stress +/- naltrexone and control +/- naltrexone) were killed every 2-3 weeks. Rats subjected to restraint stress developed a greater number of tumors earlier. Naltrexone decreased the tumor incidence in the stressed animals from 32 to 12% (P less than 0.001) and in unstressed rats from 27 to 15% (P less than 0.001) at the end of 18 weeks. Stressed rats showed a decrease of 48% (P less than 0.001) in the level of hypothalamic beta-endorphin. Plasma prolactin increased from 4-13 ng/ml in the control rats to 109-396 ng/ml (P less than 0.001) in the stressed rats throughout the 18 week period. The beneficial effect of naltrexone was associated with 42% (P less than 0.01) increase in T cell proliferation, but greater than 90% (P less than 0.001) decrease in plasma prolactin level was observed in naltrexone-treated rats compared to the untreated animals. Rats subjected to restraint stress showed a 15% (P less than 0.001) decrease in weight gain at the end of the experiment (18 weeks). Neither restraint stress nor naltrexone administration affected the caloric intake of rats during this period. Thus, we believe that restraint stress facilitates DMBA-induced mammary tumors by releasing beta-endorphin and prolactin, and naltrexone shows a beneficial effect by opposing the effect of beta-endorphin on prolactin release in the stressed animals.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Oral tolerance in experimental autoimmune encephalomyelitis: serum and salivary antibody responses.

We have recently reported that the oral administration of myelin basic protein (MBP) prior to encephalitogenic challenge results in suppression of experimental autoimmune encephalomyelitis (EAE). We examined the serum and salivary antibody responses to MBP in orally tolerant rats using an avidin-biotin enzyme-linked immunosorbent assay. Serum anti-MBP IgA and IgG, but not IgM levels are suppressed in orally tolerant versus control rats. This suppression is time dependent and is confined to the period when animals would otherwise be manifesting EAE clinical signs. In contrast, there is an increase in salivary anti-MBP IgA levels in MBP-fed rats relative to vehicle-fed controls. Thus, MBP-induced unresponsiveness is demonstrable at the humoral level, and moreover, a discrete compartmentalization between the serum and salivary anti-MBP responses exists.

Administration, Oral↗
PubMed1989

Genetic resistance in experimental autoimmune encephalomyelitis. I. Analysis of the mechanism of LeR resistance using radiation chimeras.

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease of the central nervous system that has been extensively studied in the rat. The Lewis rat is highly susceptible to the induction of EAE, while the Lewis resistant (LeR) rat is known to be resistant. In this paper, we demonstrate that the LeR rat, which was derived from the Lewis strain by inbreeding of fully resistant animals, is histocompatible with the Lewis strain. Radiation chimeras, a tool for distinguishing between immunologic and nonimmunologic resistance mechanisms, were utilized to analyze the cellular mechanisms involved in genetic resistance to EAE. By transplanting bone marrow cells from LeR rats into irradiated Lewis recipients, Lewis rats were rendered resistant to EAE induction. Likewise, transplanting Lewis bone marrow cells into irradiated LeR recipients rendered LeR rats susceptible. Mixed lymphoid cell chimeras using bone marrow, spleen, and thymus cells in Lewis recipient rats revealed individual lymphoid cell types and cell interactions that significantly affected the incidence and severity of EAE. Our results suggest that LeR resistance is mediated by hematopoietic/immune cells, and that cells located in the spleen appear to play a critical role in the resistance/susceptibility to EAE induction. Depletion of splenic adherent cells did not change the patterns of EAE resistance. In vivo cell mixing studies suggested the presence of a suppressor cell population in the LeR spleen preparations which exerted an inhibitory effect on Lewis autoimmune responses. Thus, the mechanism of LeR resistance appears to be different from that in other EAE-resistant animals.

Animals↗
PubMed1988

Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein.

The oral administration of myelin basic protein (MBP) to Lewis rats prior to an encephalitogenic challenge resulted in total inhibition or a significant delay in the onset of experimental autoimmune encephalomyelitis (EAE). In vitro lymphocyte proliferative responses to MBP were significantly decreased in MBP-fed rats when compared with vehicle-fed controls. Suppression of EAE and in vitro proliferative responses to MBP were observed to be antigen specific, since oral feeding of a control protein exerted no suppressive effect. Moreover, the specificity of MBP-induced oral tolerance was shown to be species specific, since feeding guinea pig MBP (GPMBP) or human MBP (HuMBP) induced protection only against a GPMBP or HuMBP challenge, respectively. Conversely, Lewis rats could not be orally tolerized to the self antigen rat MBP.

Administration, Oral↗
PubMed1987

Gangliosides suppress the proliferation of autoreactive cells in experimental allergic encephalomyelitis: ganglioside effects on IL-2 activity.

Gangliosides have been shown to suppress human and murine lymphocyte proliferative responses in vitro. We tested the suppressive effects of gangliosides on the proliferation of autoreactive lymphoid cells obtained from Lewis rats with experimental allergic encephalomyelitis (EAE). Exogenous rat brain gangliosides inhibited both antigen- and mitogen-induced proliferation by as much as 79 and 93%, respectively. Gangliosides similarly inhibited the antigen-induced proliferation of a myelin basic protein (MBP)-reactive T-cell line which is able to passively induce EAE. Suppression was greatest when gangliosides were added at the initiation of culture, and was not abrogated by supraoptimal antigen concentration. Interleukin 2 (IL-2) activity in culture supernatants was not diminished by the addition of gangliosides. Gangliosides did not inhibit the IL-2-induced proliferation of a murine IL-2-dependent cell line, CTLL-20, unless the IL-2 was first preincubated with gangliosides before the addition of CTLL-20. Preincubation of CTLL-20 with gangliosides resulted in no inhibition of the subsequent responses to IL-2. Exogenous gangliosides did not decrease the binding of a monoclonal antibody directed against the rat cell surface IL-2 receptor. Addition of exogenous IL-2 to ganglioside-suppressed cultures had no effect or only partially restored the proliferative responses. Therefore, gangliosides were shown to inhibit the proliferation of autoreactive lymphoid cells without affecting IL-2 production or IL-2 receptor expression.

Animals↗
PubMed1984

Modification of the clinical and histopathologic expression of experimental allergic encephalomyelitis by the vasoactive amine antagonist cyproheptadine.

Experimental allergic encephalomyelitis (EAE) is an autoimmune syndrome that can be induced in Lewis rats by myelin basic protein (BP) in complete Freund's adjuvant (CFA). Rats that have recovered from a primary episode of EAE display paradoxical long-term resistance to EAE reinduction by BP-CFA. Previous observations indicated, however, that clinical disease could be reinduced in convalescent rats by a concomitant secondary challenge with BP-CFA + Bordetella pertussis extract (PERT). Vascular permeability changes in the central nervous system (CNS) paralleled disease reinduction. To further probe the relationship between disease reinduction and vascular permeability, convalescent rats were treated with the vasoactive amine antagonist cyproheptadine (CYP) prior to a secondary challenge with BP-CFA + PERT. Data presented here indicate that CYP treatment results in substantial protection of convalescent rats from clinical disease reinduction by BP-CFA + PERT. CYP did not, however, prevent the development of new CNS lesions. CYP therapy also altered the clinical course of EAE induced by a primary injection of BP-CFA + PERT. In these rats, there was a delay in the onset of clinical signs as well as in the appearance of CNS lesions. Nevertheless, both CYP-treated and untreated naive rats challenged with BP-CFA + PERT eventually developed severe and usually lethal EAE. The effect of CYP on EAE induced in naive rats without including PERT in the sensitization protocol was also evaluated. In contrast to the mitigating effect of CYP on EAE induced or reinduced by BP-CFA + PERT, CYP treatment did not affect the clinical course or the development of CNS lesions in rats challenged with BP-CFA alone. Likewise, the passive transfer of EAE, mediated by mitogen-stimulated cells obtained from BP-CFA-sensitized donors, was not affected by CYP treatment. Collectively, these data indicate that CYP therapy altered the expression of EAE induced by regimens that included PERT, but did not affect EAE induced without PERT. In view of the opposing effects of PERT and CYP on vascular permeability, these data are consistent with the hypothesis that alterations in vascular permeability may play a crucial role in controlling the expression of autoimmune neurological diseases.

Animals↗
PubMed1984

Species-restriction of rat lymphoid cell migration inhibitory factor.

Migration inhibitory factor (MIF) was produced by lymphoid cells of Lewis rats in response to infection with Bacille Calmette Guérin (BCG), mixed lymphocyte reaction or concanavalin A stimulation. It was found that rat lymphokine-containing supernatants demonstrate a definite species specificity, in that MIF activity is observed only when rat indicator cells and not when guinea-pig indicator cells are used. A comparative study of MIF activities, using rat peritoneal exudate cells, revealed that all three methods stimulated MIF production by either spleen or lymph node cells. Only infection with BCG induced peripheral blood leukocytes to elaborate MIF. In all cases, rat MIF inhibited rat peritoneal exudate cells but not guinea-pig peritoneal exudate cells. Possible explanations for the species specificity of rat MIF including a role for receptor carbohydrate moieties and fibronectin are discussed.

Animals↗
PubMed1982

Oligoclonal IgG in rabbits with experimental allergic encephalomyelitis: non-reactivity of the bands with sensitizing neural antigens.

Oligoclonal IgG bands have recently been reported to occur in cerebrospinal fluid (CSF) and serum of rabbits with experimental allergic encephalomyelitis (EAE). To examine the specificity of these bands, a) individual bands eluted from rabbit CSF and sera were tested by radioimmunoassay (RIA) for anti-MBP activity and b) rabbit sera were absorbed with the neuroantigens used for sensitization. RIA of eluates from sequential agar gel slices of the entire IgG region of serum or CSF from MBP sensitized rabbits showed that anti-MBP activity occurred throughout the IgG region and did not localize to specific band-containing fractions. Furthermore, there was no change in banding patterns following absorption of EAE rabbit sera with washed brain homogenates, soluble MBP or MBP conjugated to Sepharose beads. Therefore, our results indicate that the oligoclonal IgG response in EAE is not preferentially directed against the sensitizing neuroantigen, and we raise the possibility of nonspecific B cell activation.

Animals↗
PubMed1981

Cerebrospinal fluid and serum oligoclonal IgG bands in rabbits with experiment allergic encephalomyelitis.

Rabbits sensitized with whole nervous tissue or myelin basic protein (MBP) plus adjuvant and developing experimental allergic encephalomyelitis (EAE) were studied for the presence of oligoclonal immunoglobulin (Ig) bands in spinal fluid and serum. Samples obtained prior to sensitization and at the time of sacrifice were concentrated and subjected to agar gel electrophoresis. Of 11 rabbits receiving whole nervous tissue and developing severe clinical signs of EAE, 7 showed new oligoclonal Ig bands in spinal fluid and in serum obtained 19 days or more after sensitization. With MBP sensitization, 2 of 6 rabbits exhibited new spinal fluid bands, while all 6 rabbits studied demonstrated serum banding. The bands were identified as IgG by immunochemical studies using peroxidase-labeled antisera and by Staph. protein A absorption. The majority of animals showed no banding in presensitization samples. The finding of oligoclonal IgG in EAE reveals yet another immunologic correlation between EAE and the human demyelinating disease, multiple sclerosis.

Animals↗
PubMed1981

Endogenous myelin basic protein-serum factors (MBP-SFs) and anti-MBP antibodies in humans. Occurrence in sera of clinically well subjects and patients with multiple sclerosis.

Sera of normal subjects and patients wtih multiple sclerosis (MS) have been frequently found to contain picomolar quantities of endogenous myelin basic protein-serum factors (MBP-SFs). These serum factors, collectively representing a heterogeneous spectrum, were detected and measured by means of a competitive inhibition radioimmunoassay (RIA) designed to distinguish their respective binding affinities with anti-MBP reagent antiserum. Anti-MBP antibodies in these same normal and patient sera were also detected and their differing binding affinities determined. In general, when sera of normal subjects were found to contain free MBP-SFs, the reagent anti-MBP antibodies in the reagent antiserum used to detect them were of relatively high binding affinity (8 X 10(8) M-1). When normal sera were found to contain free anti-MBP antibodies, the affinities of such antibodies were invariably lower (0.06-0.7 X 10(8) M-1). In contrast, sera of patients with active MS and exhibiting clinical fluctuations in their disease, infrequently contained high or medium high affinity MBP-SFs, whereas higher affinity anti-MBP antibodies were commonly detected. These patterns of MBP-SFs and anti-MBP antibodies in normal and MS human sera resemble those previously observed in studies of normal Lewis rats and rats developing experimental allergic encephalomyelitis (EAE). The findings here reported provide additional support for the view that circulating endogenous MBP-SFs may function as neuroautotolerogens that restrict expansion of MBP-reactive lymphoid cell clones having potentially injurious effector activity for central nervous system (CNS) tissue.

Adult↗
PubMed1980

Experimental allergic encephalomyelitis supernatant transfer activity (EAE-STA) in Lewis rats:immunobiologic and initial biochemical properties.

Supernatants derived from incubated lymph node cells (LNC) of Lewis rats sensitized to neuroantigen-adjuvant have the capacity to transfer experimental allergic encephalomyelitis (EAE) to syngeneic recipients. Sensitization of donors with guinea pig or rat spinal cord adjuvant by either of two routes of injection was effective in generating EAE supernatant transfer activity (EAE-STA). Despite transfer of typical EAE histopathologic lesions, which were intense and disseminated throughout the neuraxis in some animals, recipient animals invariably remained clinically well. Donor sensitization with purified myelin basic protein of guinea pig or rat origin was conspicuously ineffective in generating EAE-STA. Absorption studies revealed that EAE-STA was diminished after exposure to guinea pig or rat spinal cord or guinea pig or rat kidney, but it was not demonstrably reduced after absorption with neonatal rat spinal cord lacking encephalitogenic activity or with guinea pig or rat myelin basic protein or lysozyme. EAE-STA is stable at -20 degrees C/4 days, -70 degrees C/2 days, 4 degrees C/18 hr, and 56 degrees C/1 hr, and has a m.w. in excess of 100,000 daltons.

Absorption↗
PubMed1977

Transfer of experimental allergic encephalomyelitis in Lewis rats using supernates of incubated sensitized lymph node cells.

Supernates derived from incubated lymph node cells of Lewis rats sensitized to guinea pig spinal cord-Freund's adjuvant transfer experimental allergic encephalomyelitis (EAE) to syngeneic recipients. EAE supernatant transfer activity (EAE-STA) is not demonstrable in supernates derived from LNC of control donors not sensitized to nervous tissue. After addition of brain antigen to active supernates, EAE-STA is not longer demonstrable.

Animals↗