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Biomedical subjects

C C Whitacre

Publications and source records attributed to C C Whitacre.

At least 37 records · Page 2Linked to original sources
PubMed1996

Oral tolerance in experimental autoimmune encephalomyelitis.

In work performed by a number of laboratories, it has become quite clear that the oral administration of autoantigens exerts a profoundly suppressive effect on the development and long-term clinical course of autoimmune disease. Specific peptide sequences derived from the autoantigens are similarly suppressive. An interesting sidelight to emerge from specificity studies is that oral administration of a self-protein or peptide sequence (i.e., rat MBP peptide administered to a rat) is markedly less tolerogenic than oral administration of a non-self or even closely related sequence (guinea pig MBP peptide administered to a rat). The dose of oral antigen is now known to play a critical role in determination of the mechanism of oral tolerance, with low doses of antigen causing active suppression with concomitant release of TGFbeta1. Studies outlined here suggest that oral administration of higher antigen doses (e.g., 20 mg MBP to rats or mice) results in deletion of specific antigen-reactive T lymphocytes. This conclusion stems from the fact that injections of IL-2 could not reverse high-dose tolerance while reversing low-dose oral tolerance. Moreover, feeding MBP to MBP-TCR transgenic mice caused trafficking of transgenic cells to the intestine followed by a profound depletion of transgene-positive cells and reduction in proliferative function in all peripheral lymphoid organs. Oral tolerance has proven to be of therapeutic benefit in other animal models of autoimmune disease as well, including uveitis, collagen-induced arthritis, adjuvant arthritis, thyroiditis, myasthenia gravis, and diabetes. Initial human trials in multiple sclerosis, rheumatoid arthritis, and uveitis show promising results.

Administration, Oral↗
PubMed1996

Treatment of autoimmune disease by oral tolerance to autoantigens.

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system (CNS) which can be characterized clinically by a remitting-relapsing or a chronic progressive course. There is a striking similarity between the clinical and histopathological features of MS and the experimentally induced disease, experimental autoimmune encephalomyelitis (EAE). Induced by the injection of myelin basic protein (MBP) and adjuvants, EAE is characterized by clinical neurologic signs of paralysis and histopathologic changes consisting of perivascular mononuclear infiltration and demyelination. We have reported that the oral administration of MBP exerts a profoundly suppressive effect on EAE induced in the Lewis rat. This MBP-induced oral tolerance is characterized by an inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, a profound decrease in the T-lymphocyte proliferative response specific for the fed antigen, and a decrease in serum antibody specific for MBP. In a chronic relapsing model of EAE in the B10.PL mouse, we have shown that the oral administration of MBP either prior to MBP challenge or on the first day of clinical signs results in a decreased number and severity of EAE relapses. The oral tolerance approach has also proven effective in the suppression of other organ-specific autoimmune diseases including collagen-induced arthritis, adjuvant arthritis, uveoretinitis, experimental myasthenia gravis, diabetes, and thyroiditis as well as graft rejection. Two primary mechanisms have been proposed to explain oral tolerance in EAE-active suppression following feeding of lower doses of antigen and clonal anergy or deletion following administration of higher doses. In vivo approaches in rats and transgenic mice have been used to further explore the mechanisms underlying oral tolerance. Administration of recombinant interleukin (IL)-2 was shown to reverse the tolerance induced by feeding low doses of MBP, but not the tolerance induced by feeding high doses of MBP, indicating that deletion had occurred in the high-dose group. Moreover, the oral administration of MBP to MBP-specific T-cell receptor (TCR) transgenic mice resulted in a profound decrease of the transgenic T cells in the blood, lymph node cells (LNC), mesenteric LNC, and spleen compartments. The proliferative response to MBP was also profoundly reduced in these organs, indicating that the cells had been deleted from these sites. The results achieved in animal models have led to clinical trials of oral tolerization in three human autoimmune diseases--MS, uveoretinitis, and rheumatoid arthritis--with promising results.

Administration, Oral↗
PubMed1996

Oral tolerance in EAE: reversal of tolerance by T helper cell cytokines.

Oral administration of myelin basic protein (MBP) inhibits clinical and histopathological manifestations of experimental autoimmune encephalomyelitis (EAE), but only partially reduces serum anti-MBP antibody titers. We report here that orally administered MBP alters the isotypic distribution of anti-MBP antibody-forming cells (AFC) among various lymphoid tissues, with the most profound differences seen in mucosal tissues. We observed an isotype-selective reduction in anti-MBP IgA but not IgM AFC frequencies in Peyer's patches. The anti-MBP IgA AFC frequencies could be reconstituted by addition of interleukin 4 (IL-4) and interleukin 5(IL-5). The cytokines did not appear to generate de novo responses since no increases in anti-MBP lgA AFC frequencies were observed in control cultures. These results indicate that decreased antibody production, as a result of oral antigen administration, can be reversed by exposure to the appropriate cytokines.

Administration, Oral↗
PubMed1995

Exquisite peptide specificity of oral tolerance in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), induced in Lewis rats by injection of myelin basic protein (MBP) and adjuvant, is a T cell-mediated autoimmune disease. Earlier studies from our laboratory have shown that oral administration of guinea pig MBP before encephalitogenic challenge induces T cell anergy and results in the suppression of clinical signs and CNS histopathologic changes of EAE. In contrast, oral administration of rat MBP did not confer a similar degree of protection. This study was undertaken to determine the tolerogenicity of the synthetic peptide 68-88 derived from guinea pig (GP) MBP and rat MBP. These peptides differ by a single amino acid at position 80. Lewis rats fed GP 68-88 were protected from EAE induced with GP 68-88 or rat 68-88. In contrast, feeding rats 68-88 did not protect the animals from challenge with either peptide. Measurement of the frequency of peptide-reactive Th1 cells showed results consistent with the clinical picture. The in vitro proliferative response was significantly suppressed following oral administration of either whole GP MBP, the GP peptide, or the rat peptide, irrespective of clinical status. These results extend our earlier observation at the whole molecule level that GP but not rat MBP confers oral tolerance. These findings suggest that small structural differences at the amino acid level can produce dramatic differences in clinical outcome, with important implications for the design of multiple sclerosis clinical trials.

Administration, Oral↗
PubMed1994

Rat peritoneal mast cells present antigen to a PPD-specific T cell line.

Rat peritoneal mast cells were examined to determine whether mast cells can stimulate T cell proliferation through antigen presentation. Mast cells were obtained by peritoneal lavage and purified to 98% using density gradient centrifugation. Purified peritoneal mast cells expressed MHC class II molecules as determined by flow cytometry using monoclonal antibody OX6 specific for common determinants of rat class II. The intensity of class II expression by mast cells was not significantly increased upon incubation with recombinant rat IFN-gamma. Peritoneal mast cells also were found to express the accessory molecules ICAM-1 (CD54) and LFA-1 beta (CD18) but not LFA-1 alpha (CD11a). In the presence of antigen, purified mast cells stimulated proliferation of an autologous CD4+, PPD-specific T cell line. This stimulation was blocked by OX6 antibody, confirming that the proliferation was class II dependent. T cell proliferation was similarly induced by purified mast cell populations that were completely monocyte and macrophages depleted. These results demonstrate that mast cells, through their expression of MHC class II and accessory molecules, are capable of antigen presentation.

Animals↗
PubMed1994

Neuropsychological performance and CD4 levels in HIV-1 asymptomatic infection.

The performance of 68 HIV-1 seropositive asymptomatic (HIV+) subjects stratified on CD4 levels were compared with 82 HIV-1 seronegative (HIV-) subjects on a battery of neuropsychological, mood state, and perceived health status measures. The neuropsychological test battery included measures of attention, reaction time, memory, intellectual ability, psychomotor speed, frontal lobe or "executive" function, and decision time. None of the HIV+ subjects were taking antiviral agents. The groups did not differ for age, mood state, or WAIS-R Verbal and Performance IQ scores. Due to group differences for education and weekly ethanol consumption, both variables were used as covariates in multivariate analyses of variance. Relatively few differences were observed between subgroups of HIV+ patients or between these subgroups and control subjects. These data suggest that factors other than absolute levels of immunosuppression as expressed by CD4 levels alone, appear to be responsible for the deficits observed in HIV+ asymptomatic patients.

AIDS Dementia Complex↗
PubMed1994

Duration of illness and neuropsychological performance in asymptomatic HIV infection.

The relationship between duration of illness and neuropsychological performance was examined in 25 asymptomatic HIV-infected men with an estimated date of seroconversion. Mean duration of illness was approximately 2 years. After controlling for CD4 level at the time of neuropsychological examination, duration of illness was correlated with measures of visual attention, mental flexibility, dexterity, auditory information processing, and response fluency, as well as an overall measure of neuropsychological performance. Although these patients performed within normal limits, these data suggest that duration of infection may be related to subtle alterations in neuropsychological performance. These results are discussed with regard to possible mechanisms that implicate gradual accumulation of neurotoxins.

AIDS Dementia Complex↗
PubMed1993

Suppression of experimental autoimmune encephalomyelitis by restraint stress: sex differences.

We have recently reported that female Lewis rats exhibit significantly higher basal circadian levels of corticosterone (Cort) than male Lewis rats. The studies reported here were designed to explore whether male and female Lewis rats demonstrate a differential suppression of experimental autoimmune encephalomyelitis (EAE) following exposure to an identical regimen of repetitive restraint stress. Rats were restrained for 1 or 9 h/day beginning 5 days before myelin basic protein (MBP) challenge and extending through the recovery period (18 days post challenge). Both clinical signs and histopathological changes of EAE were more significantly suppressed in 9-h-stressed females relative to male Lewis rats. Investigation of the mechanism underlying the stress-induced suppression of EAE revealed that restraint stress did not alter the clinical course of EAE in rats challenged with MBP 68-88 encephalitogenic peptide, suggesting that restraint stress may affect processing and/or presentation of the MBP molecule. Stressed rats exhibited decreased interleukin-2 and interferon gamma production, and the frequency of MBP-reactive lymphocytes was reduced in comparison to non-stressed rats. Finally, repetitive restraint stress had no effect on blood-spinal cord permeability during EAE. The results presented here underscore the importance of such experimental variables as sex, strain, time of day, and the kinetics of immune response development.

Animals↗
PubMed1993

Neuropsychological performance in symptomatic and asymptomatic HIV infection.

OBJECTIVE: To examine cognitive function in patients at various stages of HIV infection, and to determine the nature and severity associated with stage of illness. DESIGN: Subjects were administered an extensive battery of neuropsychological tests. SUBJECTS: Two hundred and thirty-three HIV-1-infected homosexual/bisexual men and 77 HIV-negative control subjects who had been screened for previous neurological illness. All subjects were volunteers in a longitudinal study of neurobehavioral complications of HIV infection. RESULTS: Patients with symptomatic infection differed from controls on a large number of measures, and asymptomatic patients had a more circumscribed pattern of deficit. On a summary measure of cognitive impairment, there was a twofold increase in the prevalence of impairment in asymptomatic patients relative to controls, and a fourfold increase in symptomatic patients. Memory and dexterity problems appear to be early features of neurobehavioral dysfunction, and frontal lobe deficits were found in patients with symptomatic infection. CONCLUSION: These data indicate that there is a steady increase in the prevalence of neurobehavioral abnormalities associated with stage of infection. The pattern of abnormality also varies with disease stage.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Change in neuropsychological performance in asymptomatic HIV infection: 1-year follow-up.

OBJECTIVE: To examine the stability of cognitive function in patients with asymptomatic HIV infection. DESIGN: Previous longitudinal studies of cognitive function have focused on patients who progress in terms of disease stage. The present study avoided this potential confounding factor by including only subjects who remained in the asymptomatic stage of infection over the follow-up period. METHOD: Subjects were administered an extensive neuropsychological test battery at baseline and 1 year follow-up. Overall performance was characterized as normal or abnormal based on the performance of a well-matched HIV-negative control group. RESULTS: A significantly higher proportion of HIV-positive subjects became abnormal at the follow-up examination. Comparison of the seropositive subjects who remained normal with those who became abnormal revealed no differences at baseline on age, education, depression or CD4 levels. Subjects who became abnormal had worse performance at baseline on measures of information processing, verbal learning and memory, and reaction time. CONCLUSIONS: These data indicate that cognitive function may decline in some patients who continue to be in the asymptomatic stage of infection. Patients with a pattern of cognitive abnormalities at baseline, which includes information processing and reaction time deficits, may be at increased risk for declines in function during early stages of infection.

Adult↗
PubMed1993

Depression and neuropsychological performance in asymptomatic HIV infection.

OBJECTIVE: The authors examined the effect of depression on neuropsychological performance in HIV-infected men. Previous studies have suggested that depression may account for the neuropsychological abnormalities observed in some patients with HIV infection, but few studies have specifically examined this question. METHOD: An extensive neuropsychological test battery was administered to 121 HIV-seropositive asymptomatic men and 42 HIV-seronegative comparison subjects. The seropositive subjects were grouped into depressed and non-depressed groups on the basis of scores on the Beck Depression Inventory, Hamilton Rating Scale for Depression, and Structured Clinical Interview for DSM-III-R. RESULTS: Statistical comparisons revealed very few measures on which the depressed seropositive subjects scored significantly worse than either of the nondepressed comparison groups. The nondepressed seropositive group differed consistently from the seronegative comparison subjects on measures of verbal memory and dexterity. CONCLUSIONS: These data indicate that the subtle neuropsychological abnormalities observed in some asymptomatic HIV-seropositive subjects cannot be attributed to depression. These data also indicate the advantages of a multifaceted approach to assessment of depression.

Adult↗
PubMed1993

Drug and alcohol use and neuropsychological performance in asymptomatic HIV infection.

The effect of drug and alcohol abuse on neuropsychological performance was examined in 132 human immunodeficiency virus-seropositive gay or bisexual men. Syndromal (diagnostic) criteria of alcohol/drug abuse based on DSM-III-R were used, and quantitative estimates of alcohol consumption were obtained. Very few differences appeared between substance abuse subgroups formed on the basis of recency or severity of drug use. There were some correlations with the quantitative estimate of alcohol use, but not on the measures previously found to differentiate seronegative and asymptomatic seropositive gay men. These data indicate that alcohol use does affect neuropsychological performance but does not account for the differences observed in studies of seronegative and seropositive subjects.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Quantitation of antigen-specific immune responses in human immunodeficiency virus (HIV)-infected individuals by limiting dilution analysis.

The lymphocyte proliferative response to recall antigens is lost following HIV infection. We sought to devise a means by which the functional immune status of persons in the early stages of HIV infection could be monitored quantitatively. The response to tetanus toxoid was examined in 45 HIV-infected individuals and 11 controls using conventional lymphocyte proliferative assays concurrently with limiting dilution analysis utilizing the secretion of interleukin-2 as the measure of a response. Our data show that the limiting dilution analysis detects tetanus toxoid-reactive T cells in 80% of those tested, as compared to only 44% by proliferation. However, the frequency of tetanus-reactive T cells in HIV-infected individuals (median frequency = 1/59,156) is decreased five-fold as compared to seronegative controls (median frequency = 1/11,599). Longitudinal studies demonstrated a time-dependent decrease in the frequency of tetanus-specific T cell responses in the HIV-infected individuals. Thus, the limiting dilution analysis is a quantitative approach for detecting antigen-specific T cells in HIV-infected individuals, and may be used to monitor changes in T cell function in HIV infection.

CD4-Positive T-Lymphocytes↗
PubMed1992

Neuropsychological performance in asymptomatic HIV infection.

This study compared 74 human immunodeficiency virus (HIV)-negative and 131 HIV-positive asymptomatic homosexual or bisexual men on an extensive neuropsychological test battery. HIV-positive subjects' performance was significantly worse on verbal memory and psychomotor skills. The prevalence of mild but persistent neurobehavioral impairment in the HIV-positive group was approximately twice that in HIV-negative patients, consistently across several criteria for impairment. There was evidence that degree of neuropsychological impairment was related to patients' perceptions of dysfunction in daily life. Findings were not related to degree of depression or to medication effects. These data suggest that approximately 10% to 20% of HIV-positive asymptomatic men suffer mild neuropsychological impairment that influences their daily lives.

AIDS Dementia Complex↗
PubMed1991

Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy.

We have recently reported that experimental autoimmune encephalomyelitis (EAE) can be suppressed by the oral administration of myelin basic protein (MBP). The oral introduction of 20 mg MBP together with a trypsin inhibitor results in inhibition of EAE clinical signs, decreased CNS histopathologic changes and dramatically reduced MBP-specific proliferative responses in fed and challenged Lewis rats. In the present study, we have investigated the mechanism underlying MBP-induced oral tolerance in EAE. Neither lymphoid cells (lymph node cells, spleen cells, Peyer's patch lymphocytes, thymocytes) nor humoral elements derived from tolerant donors were capable of transferring the tolerance to naive recipients. Moreover, lymphoid cells obtained from orally tolerant donors exhibited a marked decrease in their capacity to transfer EAE to naive recipient rats, even after in vitro activation with MBP or Con A. We observed that EAE could be readily transferred into orally tolerant rats using MBP-specific encephalitogenic T cell lines. In vitro cell mixing studies showed that the proliferation of lymphocytes from MBP-sensitized donors was not inhibited by the addition of lymphoid cells from tolerant donors, arguing against the role of a suppressor cell. Investigation of MBP-stimulated lymphokine production showed that both IL-2 and IFN-gamma levels were substantially decreased in spleen and lymph node cell cultures from MBP-fed rats compared to vehicle-fed control animals. Furthermore, limiting dilution analyses revealed that MBP-fed rats exhibited a profound decrease in MBP-reactive, IL-2-secreting lymphocytes relative to control animals. Thus, because lymphocytes from MBP-fed rats neither proliferate nor secrete IL-2 or IFN-gamma in response to MBP and we can find no compelling evidence for the role of suppressor cells, we propose that the oral administration of MBP results in a state of clonal anergy.

Animals↗
PubMed1991

Rate of CD4 decline and neuropsychological performance in HIV infection.

This study examined the relationship between performance on a battery of neuropsychologic tasks and rate of CD4 lymphocyte decline in 47 gay or bisexual men infected with the human immunodeficiency virus type 1. Subjects were volunteers for a longitudinal study of the human immunodeficiency virus infection and were not selected because of neuropsychiatric symptoms. Subjects were at all stages of illness, although most were asymptomatic. Faster rates of decline in percent CD4 lymphocyte were related to poorer performance on measures of memory and reaction time. This relationship was independent of stage of illness and CD4 level at the time of neuropsychologic examination, and was not due to medication effects. The rate of percent CD4 lymphocyte cell loss is associated with and may represent a risk factor for the development of the human immunodeficiency virus-related neurobehavioral deficit.

Adult↗
PubMed1991

Sex and strain differences in the circadian rhythm fluctuation of endocrine and immune function in the rat: implications for rodent models of autoimmune disease.

This study compares 24-h basal patterns of corticosterone and immunoreactivity for Lewis and Fischer (F344) strain rats. Significant differences in the circadian rhythm of plasma corticosterone were found across sex and strain. Male Lewis rats exhibited significantly lower 24-h corticosterone levels relative to female Lewis and male F344 rats. In addition, male Lewis rats were found to have higher mononuclear cell counts than female Lewis or male F344 rats, particularly in the peripheral blood and spleen compartments. Levels of CD4-bearing lymphocytes in blood, lymph node, and spleen were found to be higher in Lewis rats compared to the F344 strain over a 24-h period. In general, percentages of CD8- and major histocompatibility complex (MHC) class II-bearing lymphocytes were shown to vary over 24 h in all compartments across strains. Given that the Lewis rat has low basal levels of circulating corticosterone, and comparatively higher numbers of CD4-bearing lymphocytes, these factors may play a causative role in the known susceptibility of this strain to many experimental models of autoimmune disease.

Animals↗