Biomedical subjects

P Chandler

Publications and source records attributed to P Chandler.

At least 19 recordsLinked to original sources

PubMed2001

Examination of HY response: T cell expansion, immunodominance, and cross-priming revealed by HY tetramer analysis.

We have applied MHC class I tetramers representing the two H2(b) MHC class I-restricted epitopes of the mouse male-specific minor transplantation Ag, HY, to directly determine the extent of expansion and immunodominance within the CD8+ T cell compartment following exposure to male tissue. Immunization with male bone marrow (BM), spleen, dendritic cells (DCs) and by skin graft led to rapid expansion of both specificities occupying up to >20% of the CD8+ T cell pool. At a high dose, whole BM or spleen were found to be more effective at stimulating the response than BM-derived DCs. In vivo, immunodominance within the responding cell population was only observed following chronic Ag stimulation, whereas epitope immunodominance was established rapidly following in vitro restimulation. Peptide affinity for the restricting MHC molecule was greater for the immunodominant epitope, suggesting that this might be a factor in the emergence of immunodominance. Using tetramers, we were able to directly visualize the cross-primed CD8+ HY response, but we did not find it to be the principal route for MHC class I presentation. Immunization with female spleen or DCs coated with the full complement of defined HY peptides, including the A(b)-restricted CD4+ Th cell determinant, failed to induce tetramer-reactive cells.

Animals↗

PubMed2001

Rapid rejection of HLA-A2 transgenic skin graft due to indirect allorecognition.

BACKGROUND: At present, it is not clear whether xenogeneic MHC molecules are recognized by T cells directly or indirectly through self-MHC-restricted presentation in a transplantation setting. METHODS: We have transplanted skin from HLA-A2 transgenic (B6.A2) to nontransgenic C57BL/6 (B6) mice and investigated the subsequent mouse T-cell responses to HLA molecules, in vivo and in vitro. RESULTS: Skin transplanted from transgenic B6.A2 to B6 mice was rejected rapidly, in 12-16 days. Although naive B6 mice did not respond to B6.A2 splenocytes in vitro, spleen cells from mice that underwent transplantation showed strong proliferative responses. An anti-B6.A2 T-cell line from mice that underwent transplantation made proliferative responses to B6.A2 splenocytes but did not recognize HLA-A2 on human cells or transfected allogeneic mouse cells. The indirect, self-H-2-restricted recognition of HLA-A2 implied by this was confirmed by the finding that lysates of HLA-A2-positive, but not HLA-A2-negative, human B cells were stimulatory when pulsed onto syngeneic antigen-presenting cells and by inhibition of anti-B6.A2 proliferation with both anti-mouse MHC class I and class II antibodies. CONCLUSION: Our results suggest that indirect recognition of xenogeneic MHC antigen plays a predominant role in graft rejection.

Animals↗

PubMed2001

Genetic analysis of a new mouse model for non-insulin-dependent diabetes.

The TallyHo (TH) mouse strain is a newly established model for non-insulin-dependent diabetes mellitus (NIDDM). TH mice show obesity, hyperinsulinemia, hyperlipidemia, and male-limited hyperglycemia. A genetic dissection of the diabetes syndrome has been carried out using male backcross 1 progeny obtained from crosses between (C57BL/6J x TH)F1 and TH mice or (CAST/Ei x TH)F1 and TH mice. A genome-wide scan reveals three quantitative trait loci (QTLs), Tanidd1-3 (TH-associated NIDDM) linked to hyperglycemia. The major QTL (common in both crosses), Tanidd1, maps to chromosome (Chr) 19. Additionally, gene-gene interactions contributing to hyperglycemia have been observed between Tanidd1 and a locus on Chr 18 as well as between Tanidd2 and a locus on Chr 16. The overt hyperglycemia in TH mice is, therefore, likely due to a mutation in a major diabetes susceptibility locus on Chr 19, which interacts with additional genes to lead to an observable phenotype.

Animals↗

PubMed2001

Learning by imagining.

Five experiments were conducted to investigate the relative effectiveness of 2 alternative instructional strategies. Students who were engaged in studying worked examples that emphasized understanding and remembering procedures and concepts were compared with students who were engaged in imagining worked examples that emphasized imagining procedures and concepts. It was hypothesized that students who held prerequisite schemas would find imagining to have a beneficial effect on learning, compared with studying the material, whereas students who were less knowledgeable would find imagining to have a negative effect on learning, compared with studying. Experimental results were in accord with our hypotheses. It was concluded that, under specific circumstances, encouraging students to imagine procedures and concepts can substantially facilitate learning.

Adolescent↗

PubMed2001

Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy.

Indoleamine 2,3 dioxygenase (IDO) activity during pregnancy protects developing fetuses from maternal immune responses in CBA mice. We show here that fetal allografts were rejected only in mating combinations where paternally inherited tissue antigens elicited potent maternal T cell responses after exposure to IDO inhibitor. IDO inhibitor treatment triggered extensive inflammation at the maternal-fetal interface in susceptible mating combinations, which was characterized by complement deposition and hemorrhagic necrosis. Identical inflammatory responses occurred in B cell-deficient (RAG-I-/-) mothers that carried a monoclonal cohort of CD8+ T cells specific for a single paternally inherited fetal major histocompatibility complex antigen. Thus, fetal allograft rejection was accompanied by a unique form of inflammation that was characterized by T cell-dependent, antibody-independent activation of complement. In contrast, no inflammation, complement deposition or T cell infiltration was elicited when mice carrying syngeneic fetuses were exposed to IDO inhibitor. These data show that IDO activity protects the fetus by suppressing T cell-driven local inflammatory responses to fetal alloantigens.

Animals↗

PubMed2001

Measuring adherence to a women's walking program.

The purpose of this study is to demonstrate the use of a self-report exercise log and a heart-rate monitor in the measurement of adherence to the dimensions of an exercise prescription and to propose an alternative way to define adherence to a 24-week home-based women's walking program, which reflects the dynamic process of behavior change. Adherence was measured with exercise logs, Polar Vantage XL Heart-Rate Monitors, and pre- to postintervention change in VO2 max. Of the dimensions of the exercise prescription, frequency of walks documented by both the heart-rate monitor and the exercise log had a higher correlation than duration and intensity of walking, with change in VO2 max suggesting that frequency was potentially the most predictive adherence measure. Examination of the total number of walks and the number and sequence of weeks without walks over the 24-week intervention revealed dynamic patterns of adherence suggesting variation in the degree of behavioral change.

Aged↗

PubMed2000

The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen.

The mammalian Y chromosome encodes male-specific minor histocompatibility (H-Y) Ags that are recognized by female T cells in an MHC-restricted manner. Two human H-Y epitopes presented by HLA-A2 and HLA-B7, respectively, have been identified previously and both are derived from the SMCY gene. We previously isolated CD8+ CTL clones that recognized a male-specific minor histocompatibility Ag presented by HLA-B8. In contrast to the SMCY-encoded H-Y epitopes, the B8/H-Y Ag was not presented by fibroblasts from male donors, suggesting that it was encoded by a novel gene. We now report that the HLA-B8-restricted H-Y epitope is defined by the octameric peptide LPHNHTDL corresponding to aa residues 566-573 of the human UTY protein. Transcription of the UTY gene is detected in a wide range of human tissues, but presentation of the UTY-derived H-Y epitope to CTL by cultured human cells shows significant cell-type specificity. Identification of this CTL-defined H-Y epitope should facilitate analysis of its contribution to graft/host interactions following sex-mismatched organ and bone marrow transplantation.

Amino Acid Sequence↗

PubMed2000

Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice.

OBJECTIVE: To identify intervals containing systemic lupus erythematosus (SLE) susceptibility alleles in the BXSB strain of mice. METHODS: We analyzed 286 (B10 x [B10 x BXSB]F1) backcross mice for a range of phenotypic traits associated with the development of SLE in BXSB mice. The mice were genotyped using 93 microsatellite markers, and the linkage of these markers to disease was studied by extreme-phenotype and quantitative trait locus analysis. RESULTS: The disease phenotype in these backcross mice was less severe than that in BXSB mice. However, antinuclear antibody production was increased compared with the parental strain. We identified 4 areas of genetic linkage to disease on chromosome 1 (Bxs1-4), 1 on chromosome 3 (Bxs5), and another interval on chromosome 13 which were associated with various aspects of the phenotype. Bxs4 and Bxs5 are located in regions not previously linked to disease in other models of SLE. CONCLUSION: SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. There is evidence that different intervals affect particular aspects of the SLE phenotype.

Alleles↗

PubMed2000

Absence of in vitro or in vivo bystander effects in a thymidine kinase-transduced murine T lymphoma.

Among the goals of an optimal gene transfer system are a predictably high efficiency of transfer and the ability to confer stable gene expression. An additional benefit of strategies designed to target tumor or effector cells could be the induction of a bystander effect. Although tumor killing by the bystander effect in vivo has been obtained in several types of malignant tumors, it has not been reported for T lymphomas. The goals of this work were to determine the stability of the expression of the herpes simplex virus type-1 thymidine kinase and the low-affinity receptor for nerve growth factor truncated of its intracellular domain (deltaLNGFR) genes inserted in a murine T lymphoma; in addition, we sought to determine whether a bystander effect (direct or indirect) was present after treatment of the transduced tumor with ganciclovir. This study demonstrates a high level of stable expression of both genes in the T lymphoma in vitro and in vivo. However, we could not detect direct or indirect bystander effects in vivo mediated by the herpes simplex virus thymidine kinase/ganciclovir system in this tumor of lymphocyte origin. This is the first report to investigate bystander effects in vivo on a T-cell lineage tumor; in addition, this report has implications for the therapeutic transfer of non-transformed, antigen-specific T cells in vivo.

Animals↗

PubMed1999

Thymocyte antigens do not induce tolerance in the CD4+ T cell compartment.

Thymocytes fail to tolerize the developing T cell repertoire to self MHC class I (MHC I) Ags because transgenic (CD2Kb) mice expressing H-2Kb solely in lymphoid cell lineages reject skin grafts mismatched only for H-2Kb. In this study, we examined why thymocytes fail to tolerize the T cell repertoire to self MHC I Ags. The ability of CD2Kb mice to reject H-2Kb skin grafts was age dependent because CD2Kb mice older than 20 wk accepted skin grafts. T cells from younger CD2Kb mice proliferated, but did not develop cytotoxic functions in vitro in response to H-2Kb. Proliferative responses were dominated by H-2Kb-specific, CD4+ T cells rather than CD8+ T cells. Representative CD4+ T cell clones from CD2Kb mice were MHC II restricted and recognized processed H-2Kb. TCR transgenic mice were generated from one CD4+ T cell clone (361) to monitor development of H-2Kb-specific immature thymocytes when all thymic cells or lymphoid cell lineages only expressed H-2Kb. Thymocyte precursors were not eliminated and mice were not tolerant to H-2Kb when Tg361 TCR transgenic mice were intercrossed with CD2Kb mice. In contrast, all thymocyte precursors were eliminated efficiently in thymic microenvironments in which all cells expressed H-2Kb. We conclude that self MHC I Ags expressed exclusively in thymocytes do not induce T cell tolerance because presentation of processed self MHC I Ags on self MHC II molecules fails to induce negative selection of CD4+ T cell precursors. This suggests that some self Ags are effectively compartmentalized and cannot induce self-tolerance in the T cell repertoire.

Animals↗

PubMed1999

Anergic T cells act as suppressor cells in vitro and in vivo.

The potential suppressive effects of allospecific anergic T cells were investigated both in vitro and in vivo. Allospecific T cells were rendered unresponsive in vitro using immobilized anti-CD3 mAb. These anergic T cells profoundly inhibited proliferation of responsive T cells in an antigen-specific manner. The observed inhibition did not appear to be due to the release of inhibitory cytokines in that secretion of IL-2, IFN-gamma, IL-4, IL-10 and TGF-beta was greatly reduced following the induction of anergy, and neutralizing mAb specific for IL-4, IL-10 and TGF-beta failed to reverse the inhibition. Furthermore, the suppression mediated by anergic T cells required cell to cell contact. In vivo, adoptive transfer of anergic T cells into recipients of allogeneic skin grafts led to prolonged skin graft survival. Consistent with the lack of inhibitory cytokine production by the anergic cells, prolongation of skin allograft rejection was not influenced by the simultaneous administration of a neutralizing anti-IL-4 antibody. These results indicate that anergic T cells can function as antigen-specific suppressor cells both in vitro and in vivo.

Animals↗

PubMed1999

Women's occupations, energy expenditure, and cardiovascular risk factors.

The purpose of this study was to examine the cardiovascular risk factors and energy expenditure of women from occupations that differ by physical activity level and socioeconomic level. Participants included 171 women randomly selected from employee lists at 10 employment sites. Measures included blood pressure, body mass index, levels of total and high-density lipoprotein (HDL) cholesterol, a submaximal aerobic fitness test on a bicycle ergometer, and a 12-month retrospective self-report of occupational, leisure time, and household energy expenditure. Women in active occupations had lower total cholesterol and higher HDL cholesterol than women in sedentary occupations. Women with higher occupational energy expenditure scores had higher HDL cholesterol and lower total cholesterol than women with lower occupational energy scores. Findings suggest that cardiovascular benefits, particularly for lipid profiles, may be derived from even small increases in occupational physical activity. The workplace may offer an environment for initiating policies to facilitate increased physical activity among women.

Activities of Daily Living↗

PubMed1999

Melanosis of the uterine cervix: a report of two cases and discussion of pigmented cervical lesions.

Two cases of cervical melanosis, an uncommon process characterized by hyperpigmentation of the basal epithelium, with or without accompanying basal melanocytes, are reported. The etiology of cervical melanosis is uncertain but may represent a metaplastic change in response to trauma or chronic irritation. On gross examination, it is not possible to reliably separate the different causes of cervical pigmentation; consequently, any pigmented cervical lesion should be biopsied.

Adult↗

PubMed1998

Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice.

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 x BXSB)F1 and (BXSB x (B10 x BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (chi(2) = 15.68, p = 7.5 x 10(-5)), as was D1Mit12 at 63.1 cM (chi(2) = 20.17, p = 7.1 x 10(-6)). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (chi(2) = 17.28, p = 3.2 x 10(-5)). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.

Animals↗

PubMed1998

Rejection of H-Y disparate skin grafts by monospecific CD4+ Th1 and Th2 cells: no requirement for CD8+ T cells or B cells.

We wished to determine whether CD4+ T cells could reject a skin graft that was discordant for a single minor transplantation Ag in the absence of CD8+ T cells or Ab. Transgenic A1(M) mice were constructed that express the rearranged V beta 8.2 and V alpha 10 TCR genes from a T cell clone that is specific for the male Ag (H-Y) in the context of H2-Ek. In addition, the RAG-1(-/-) background was bred onto these mice to eliminate any endogenous TCR rearrangements. As expected, clonal deletion was found to be complete in the thymus of male A1(M) x RAG-1(-/-) mice, while only CD4+ T cells were positively selected and found in the periphery of females. Female A1(M) x RAG-1(-/-) mice were able to rapidly reject (in <14 days) male (but not female) skin grafts in a CD4-dependent fashion. After multiple grafts, it was confirmed that no CD8+ T cells or surface Ig+ B cells were present. An immunofluorescent analysis of spleen cells after grafting showed that the majority of T cells expressed activation markers (CD44, CD25, and intracytoplasmic IL-2) and a significant proportion were making IFN-gamma and IL-4. Surprisingly, the transfer of either Th1 or Th2 CD4+ T cell lines from these mice into T cell-depleted recipients was sufficient to cause a specific rejection of male skin.

Animals↗

PubMed1998

Family systems therapy after Operation Desert Storm with European-theater veterans.

We describe a quasi-experimental trial of time-limited family therapy with veterans and families of veterans who served in Europe, outside the war zone, during Operation Desert Storm (ODS). Family systems therapy was provided both to individuals and conjointly to couples or families during the acute postwar readjustment period. The intervention adapted strategies from structural, strategic, intergenerational, and behavioral family therapies in a brief-treatment protocol for systemic stressor resolution. Veterans given family system therapy were able to resume functional levels of psychosocial adjustment and reduce the risk of long-term (chronic or delayed) psychosocial impairment. Based on these preliminary findings, controlled evaluation of family systems therapy appears warranted for individuals and families exposed to subtraumatic stressors such as wartime non-war-zone military deployment.

Adult↗

PubMed1998

Sociodemographic characteristics, biological factors, and symptom reporting in midlife women.

OBJECTIVE: The purpose of this study is to examine the influence of sociodemographic characteristics, reproductive hormones, and body composition on symptoms reported by generally well midlife women. DESIGN: The design was a 24-cell, randomly selected quota sample, stratified by four occupations that varied in professional status, two races, and three age groups. One hundred fifty-three women, aged 35 to 69, who worked 20 or more hours a week, who were not on hormone replacement therapy, who were not pregnant, and who did not have a hysterectomy prior to the age of 53 participated in the study. Data were collected at 10 employment sites. Symptoms were assessed by a 22-item symptom index. Serum hormone levels of estradiol and follicle stimulating hormone (FSH) were drawn for each woman, and body composition was assessed by body mass index (BMI). RESULTS: Chi-square tests showed that significantly more White women than Black women experienced nervous tension, loss of urine, and vaginal dryness. Analyses of variance showed that women experiencing hot flashes had significantly higher FSH levels, lower estradiol levels, and higher BMI than women not experiencing this symptom. Estradiol (odds ratio 0.988) and BMI (odds ratio 1.094) were significant predictors of experiencing hot flashes when entered into a stepwise logistic regression with age and FSH level as covariates. CONCLUSIONS: Findings suggest that symptoms experienced by midlife women are consistent across races, and that interventions targeting weight reduction may improve hot flashes experienced by midlife women.

Adult↗

PubMed1998

Social role quality and psychological well being in employed black and white midlife women.

This study examined relationships among job, partner, and parent role quality and psychological well being in midlife black (n = 51) and white (n = 56) women employed in occupations varying by socioeconomic status (SES). Oversampling for black women ensured balanced occupational representation, allowing investigation uncontaminated by SES. Instruments included Baruch and Barnett's Rewards and Concerns Scales, Bradburn Affect Balance Scale, and Center for Epidemiological Studies Depression Scale (CES-D). Better well being scores were reported by black women than whites, and by professionals than non-professionals. However, when race, occupational group, and menopausal status were held constant in a multiple regression analysis, partner role quality was significantly related to both well being scores, parent role quality was related to life satisfaction only, and job role quality was not related to either. Nurses in the workplace can help women identify problematic aspects of their multiple social roles, and facilitate resolution of problems to improve worker health.

Adult↗