Euthymic Controls Research Articles

0199 Effects of acute sleep deprivation on cognitive performance in depressed individuals

Abstract Introduction Acute sleep deprivation (SD) is an effective, rapid antidepressant treatment. However, SD has adverse effects on cognitive performance. The effects of SD on cognitive performance in depression remain underexplored. This study investigated relationships between depression and performance on Cognition – a neurocognitive battery of 10 tests that cover a range of cognitive domains – during acute SD. Methods Thirty-six individuals with current depression (69.4% female; 33±9.5 yrs) and 10 euthymic controls (40% female; 35±9.5 yrs) underwent a baseline night of sleep followed by 36 hours SD in the laboratory. Participants completed the Cognition battery twice after each protocol night. Each of the 10 Cognition tests has two separate metrics of performance: speed and accuracy. Multivariable linear regressions were used to assess effects of depression status, age, and gender on each performance metric at baseline. Mixed effects models were used to assess effects of depression status, sleep deprivation, and their interaction on performance metrics. All models included a random effect over participants and were adjusted for age, gender, and time of day. Results At baseline, depressed individuals were significantly faster than controls on three tests of working memory (β=-72.6; p=0.03), spatial orientation (β=-2944.7; p=0.01), and emotion recognition (β=-537.5; p=0.005) respectively, although these effects did not survive correction for multiple comparisons. Mixed effects model results revealed a significant effect of depression status on the speed metric from the spatial orientation test, whereby depressed individuals were faster across the protocol (β=-2579.6; p=0.04) and a significant interaction effect between depression status and study day on the speed metric from a risk-taking behavior test, whereby depressed individuals were slower after SD (β=480.9, p=0.01); neither effect survived correction for multiple comparisons. However, sleep deprivation was significantly associated with reductions in performance in models for 10 out of 20 metrics (all adjusted ps < 0.05). Conclusion These results suggest that currently depressed individuals exhibit the same decrements in cognitive performance after acute SD as non-depressed individuals. Future analyses will examine whether baseline depression severity predicts cognitive performance and whether differences in performance exist between SD responders versus non-responders. Support (if any) This work was supported by the National Institute of Mental Health (R01MH107571).

Loss of thymic function promotes EAE relapse in anti-CD52-treated mice

Anti-CD52 treatment creates a long-lasting CD4 T cell lymphopenia and reduces multiple sclerosis (MS) relapses in humans. In contrast, anti-CD52 therapy at disease onset more fully suppresses experimental autoimmune encephalomyelitis (EAE) in mice, and T cell repopulation is rapid. To test whether prolonged T cell lymphopenia promotes relapses, we thymectomized mice prior to EAE induction and anti-CD52 treatment. Thymectomy greatly reduced the number of recent thymic emigrant T cells and was associated with a prolonged reduction in CD4 T cells in peripheral blood. Two-thirds of thymectomized C57BL/6 mice had an EAE relapse post anti-CD52 treatment, while no surgery and sham surgery euthymic controls remained relapse-free. These data demonstrate that thymus function can alter the effectiveness of anti-CD52 treatment.

Disclosing Default Mode Network on Euthymic Bipolar Patients and Healthy Controls: A Combined Approach to Resting State fMRI Data

Disclosing Default Mode Network on Euthymic Bipolar Patients and Healthy Controls: A Combined Approach to Resting State fMRI Data

Mood disorders increase mortality mainly through dementia: A community-based prospective cohort study.

The effects of mood disorders on mortality may be mediated by their effects on the risk of dementia, and interventions to reduce the occurrence of dementia may reduce their overall mortality. This study aimed to investigate the direct effects of depressive and bipolar disorders on the 6-year risk of mortality and also their indirect effects on mortality due to their effect on the risk of dementia. A total of 5101 Koreans were selected from a community-based prospective cohort study, and 6-year risks of mortality and dementia in participants with depressive and bipolar disorders were estimated by Cox proportional hazard analysis. The direct and indirect effects of depressive and bipolar disorders on the risk of mortality were estimated using structural equation modeling. The depressive and bipolar disorder groups showed 51% and 85% higher 6-year mortality, and 82% and 127% higher risk of dementia, respectively, compared to euthymic controls. The effects of depressive and bipolar disorders on mortality were mainly mediated by their effects on the risk of dementia in a structural equation model. The direct effects of each mood disorder on mortality were not significant. Both depressive and bipolar disorders increased the risks of mortality and dementia, and the effects of mood disorders on mortality were mainly mediated through dementia. As dementia occurs later in life than mood disorders, measures to prevent it may effectively reduce mortality in individuals with a history of mood disorders, as well as being more feasible than attempting to control other causes of death.

Retrospective follow-up analysis of the transcriptomic patterns of cytokines, cytokine receptors and chemokines at preconception and during pregnancy, in women with post-partum depression.

Post-partum depression (PPD) occurs in approximately 20% of women usually early following child delivery. PPD represents an important unmet medical need as it is frequently underdiagnosed and, as the neurobiology of the disease is limitedly known, no pathogenic-tailored approach is available and only symptomatic medications are used. In the present study, we carried out a DNA microarray analysis to evaluate the fluctuation of cytokines, cytokine receptors and chemokines during the preconception period, the 1st and 3th trimester of pregnancy and the early post-partum period. The data demonstrated that, as compared to always-depressed patients and euthymic controls, women who developed PPD exhibited significant fluctuations in the levels of different cytokines and cytokine receptors, primarily related to tumor necrosis factor (TNF) and interleukin (IL)18. These data emphasize the role of the immune system in PPD. However, additional studies aimed at evaluating if and how these functional modifications of the immune system during pregnancy are related to the development of PPD warranted to confirm our findings.

Assessment of linear and nonlinear/complex heartbeat dynamics in subclinical depression (dysphoria)

Objective: Depression is one of the leading causes of disability worldwide. Most previous studies have focused on major depression, and studies on subclinical depression, such as those on so-called dysphoria, have been overlooked. Indeed, dysphoria is associated with a high prevalence of somatic disorders, and a reduction of quality of life and life expectancy. In current clinical practice, dysphoria is assessed using psychometric questionnaires and structured interviews only, without taking into account objective pathophysiological indices. To address this problem, in this study we investigated heartbeat linear and nonlinear dynamics to derive objective autonomic nervous system biomarkers of dysphoria. Approach: Sixty undergraduate students participated in the study: according to clinical evaluation, 24 of them were dysphoric. Extensive group-wise statistics was performed to characterize the pathological and control groups. Moreover, a recursive feature elimination algorithm based on a K-NN classifier was carried out for the automatic recognition of dysphoria at a single-subject level. Main results: The results showed that the most significant group-wise differences referred to increased heartbeat complexity (particularly for fractal dimension, sample entropy and recurrence plot analysis) with regards to the healthy controls, confirming dysfunctional nonlinear sympatho-vagal dynamics in mood disorders. Furthermore, a balanced accuracy of 79.17% was achieved in automatically distinguishing dysphoric patients from controls, with the most informative power attributed to nonlinear, spectral and polyspectral quantifiers of cardiovascular variability. Significance: This study experimentally supports the assessment of dysphoria as a defined clinical condition with specific characteristics which are different both from healthy, fully euthymic controls and from full-blown major depression.

C-reactive protein levels are related to suicidality in euthymic patients with bipolar disorder

IntroductionImmune alterations are believed to be an important part in etiopathogenesis of affective disorders. However, it is not clear if the altered immune mediators are related to distinct disorders or particular psychopathology.AimsThe aim of our study was to explore the differences in C-reactive protein levels (CRP) between euthymic BD patients and healthy controls, as well as to explore the relationship between CRP and lifetime presented psychopathology within BD.MethodsThe study group consisted of 83 patients diagnosed with BD, compared to the healthy control group (n = 73) and matched according to age, gender, and body mass index (BMI). Lifetime psychopathology has been assessed according to predominant polarity as well as previous history of suicide attempts and psychotic episodes.ResultsThe CRP levels were significantly higher in BD patients when compared to healthy controls. After covarying for confounders, we observed that CRP levels, in euthymic BD patients, were related to number of previous suicide attempts, but not other indicators of lifetime psychopathology.ConclusionsBD patients per se, and particularly those with more suicide attempts, are more likely to present with proinflammatory state, even when in remission. Previous history of suicide attempts could bear specifically vulnerable endophenotype within BD. Systemic, longitudinal monitoring of the course of illness, and potential inflammatory mediators that underlie its systemic nature is warranted.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation

Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.

Immune system and bone metabolism: Does thymectomy influence postmenopausal bone loss in humans?

Recent studies of animal models have suggested that an increase in the number of T cells due to both peripheral expansion and increased thymic T cell output plays a key role in the regulation of bone loss after ovariectomy. Osteoclastogenic cytokines which are either produced by T cells or activate T cells have also been implicated in ovx induced bone loss. Among them are TNF alpha and IL-7. The present study investigates the role of thymectomy (THX) and IL-7 in bone metabolism in humans. We studied T cells subsets, cytokine production and bone metabolism in 13 women thymectomized for Myasthenia gravis as compared to healthy controls. Our data demonstrate that the number of CD4+ and TNF-producing T cells is lower in THX women as compared to euthymic controls. However in THX women the residual T cells produce higher levels of IL-7 and RANKL. Furthermore, flow cytometry shows that IL-7 is produced by T and B cells. Serum levels of TNF alpha were unaffected by THX and both serum TNF alpha and the RANKL/OPG correlated inversely with BMD. There were no differences in bone turnover and bone mineral density between THX women and the controls. These data suggest that THX decreases the number of TNF-producing CD4+ T cells but does not alters serum TNF levels. The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL. Further studies are needed to clarify the role of thymus in bone metabolism and osteoclastogenesis in postmenopausal women.

Executive and visuospatial sketchpad resources in euthymic bipolar disorder: Implications for visuospatial working memory architecture

Visuospatial working memory theory is used to interpret the cognitive impairment in euthymic bipolar disorder. Such patients show deficits in the Corsi Blocks Test (CBT) and executive control. To understand these deficits, 20 euthymic bipolar patients and controls were administered the CBT, Visual Patterns Test (VPT), and a new visual memory task designed to make minimal demands on executive resources. Initial analyses validated the visual memory task and implicated executive involvement in the CBT and VPT. Subsequent analyses on a number of tests confirmed CBT and executive deficits while performance was normal on the VPT and visual memory test. ANCOVA indicated that impaired executive function underpinned patients’ CBT performance. Implications for the interface between executive and slave systems of working memory are discussed.

Host thymectomy and cyclosporine lead to unstable skin graft tolerance after class I mismatched allogeneic neonatal thymic transplantation in mice

Background Our laboratory has demonstrated that xenogeneic porcine thymus tissue grafted in thymectomized (ATX) and T cell-depleted mice induces donor-specific tolerance. Recipient thymectomy is essential for the success of tolerance induction. In contrast, studies in pigs grafted with non-vascularized allogeneic class I mismatched thymus tissue under the cover of CyA have shown that removal of host thymus is detrimental to thymic graft survival. To determine the requirements for nonvascularized allogeneic class I-mismatched thymic engraftment in mice, we performed thymic allotransplantation under the cover of CyA. Materials and methods Euthymic and ATX B10.MBR mice received class I mismatched B10.AKM neonatal mouse thymus (NMTHY) tissue under the kidney capsule with or without a short course of CyA. The grafts were allowed to engraft for two and a half months before exploratory laparotomy was performed to evaluate them. Three months after the thymic transplant, mice were challenged with donor-specific skin grafts to assess tolerance. One month after donor-specific skin grafting, they received third party B10.BR skin grafts. Cellular anti-donor immune responses were studied at the time of euthanasia. Results CyA-treated ATX and euthymic control mice showed good engraftment of the allogeneic thymic tissue at the time of exploratory laparotomy, whereas non-CyA-treated ATX and euthymic controls had rejected the grafts. The CyA-treated ATX B10.MBR mice accepted donor-specific skin grafts, but rejected them following a challenge with third party B10.BR skin grafts. Untreated ATX and euthymic mice and 6 of 7 CyA-treated euthymic mice rejected donor skin within 15 days. Mixed lymphocyte reactions did not show an increased anti-donor response, but CML clearly showed sensitization and increased killing activity against donor-type targets in these mice. Conclusion Allogeneic thymic transplantation across a class I MHC barrier under the cover of CyA induces a metastable state of tolerance in mice. To achieve this state, ATX of the recipient is required.

High harm avoidance and low self-directedness in euthymic young adults with recurrent, early-onset depression

Background The personality dimensions of harm avoidance (HA) and self-directedness (SD), as measured by the Temperament and Character Inventory (TCI), have been widely associated with depression and there is preliminary evidence that they may represent trait markers for depression. However, many studies in this area are limited by the use of heterogeneous samples of depressed patients and by the confounding effect of depressed mood during personality testing. The current study compares TCI personality dimension scores in a group of euthymic young adults with recurrent early-onset major depressive disorder (RE-MDD) to well-matched euthymic controls. Methods Fifty-two young adults with a past history of RE-MDD were recruited from consecutive referrals to a psychiatric clinic at a university health service. Eighty nine controls were also recruited. Euthymia was established in patients by a score of less than 9 on the Hamilton Rating Scale for Depression (HRSD) and in controls by a Becks Depression Inventory (BDI) score of less than 10. All participants completed the TCI-125. Results Patients and controls were well matched in terms of sociodemographic profile. Euthymic RE-MDD patients scored significantly higher than controls on the temperament dimension of harm avoidance (HA; mean score 14.5 versus 7.8, p < 0.0001) and significantly lower than controls on the character dimension of self-directedness (SD; mean score 14.1 versus 19.9, p < 0.0001). Covariance analysis suggested that both HA and SD contributed independently to the familial risk of depression. Limitations Subjects and controls all came from relatively affluent social backgrounds—these findings may not generalise to more socioeconomically diverse populations. The possibility of a ‘scarring effect’ of depressive episodes on self-reported personality dimension scores cannot be excluded. Conclusions High HA and low SD represent trait markers for liability to recurrent major depressive disorder in young adults. Further research is needed to replicate these findings and to assess the contribution that the experience of depressive episodes makes to self-reported personality dimension scores.

THE ROLE OF HOST THYMIC FUNCTION IN THE INDUCTION OF TOLERANCE ACROSS FULL MHC BARRIERS BY FK506

P929 Aims: Previous studies have demonstrated the importance of an intact thymus in induction of tolerance to class I-mismatched renal allografts by Cyclosporin in miniature swine. A short course of FK506 has subsequently been shown to induce tolerance to fully mismatched renal allografts in this large animal model. In the present study, we assessed whether thymectomy likewise interferes with induction of this tolerance. Methods: Recipients of fully MHC disparate renal allografts were treated with a 12-day course of FK506 (0.15 mg/kg/day by continuous i.v. infusion), with doses adjusted to maintain trough levels of 30-50 ng/ml. Four experimental animals were thymectomized 21 days prior to transplantation, while two control animals remained euthymic. Tolerance was tested in vivo in animals with surviving grafts at day 100 by re-transplantation using another donor-matched kidney and no immunosuppression. Results: Both euthymic controls accepted their renal allografts for >100 days and accepted second grafts long-term with stable renal function. They also demonstrated donor-specific hypo-responsiveness in CML and MLR assays and showed no evidence of IgG or IgM deposition in kidney biopsies, confirming that they were tolerant. In contrast, all four thymectomized recipients developed evidence for acute and chronic rejection. The first animal rejected its graft on day 17, autopsy demonstrating a swollen and necrotic graft with patent vessels. The second animal maintained its kidney >100 days, but rejected a second donor-matched allograft acutely on day 20. The third animal was euthanized on day 99 due to chronic rejection with unstable renal function. The fourth animal accepted both its first and second renal allografts, but remnants of the native thymus were detected on autopsy, indicating incomplete thymectomy. In vitro assays of the first three (but not the fourth) animals demonstrated responsiveness to donor MHC by CML and MLR and both IgG and IgM deposition were found in the kidneys histologically. Conclusions: The host thymus is required for induction of transplant tolerance across a two-haplotype full MHC barrier by a short course of FK506, although even a small amount of thymic tissue may be sufficient to provide the required thymic function.

Event-Related Potentials and Cognitive Processing of Affectively Toned Words in Depression

Abstract Background: Depressed subjects and euthymic controls demonstrate differences in cognitive processing and brain electrophysiology. Contingent negative variation (CNV) and postimperative negative variation (PINV) was used to investigate the relationship between cognition and cortical event related potentials. Method: Electrophysiological responses and memory of different personality trait adjectives were measured in 15 patients with major depressive disorder and 15 euthymic controls. The words were presented acoustically to elicit event-related potentials. The subjects were asked to indicate whether the words were self-referential. Responses were measured separately for self referential and non-self referential, neutral, positively and negatively toned words. Results: Depressed patients chose more negative and fewer positive words as self-referential, though no significant differences between groups in CNV magnitude for any of the words were found. Persistence of cortical negativity after the motor response (PINV) was significantly (P &lt; 0.02) greater in patients for all non-self-referential words, and reaction times were significantly longer for all words. Recall of positive words and recognition of all words were significantly impaired in patients. Conclusions: Both electrophysiological measures and memory tests found differences between depressed patients and controls, suggesting that the PINV wave may be a useful electrophysiological probe to clarify the neurophysiological basis of cognitive processes.

277. Open adjunctive gabapentin effective in bipolar depression

resolved during euthymia and hypomania in a case report of a rapid cycling bipolar disorder patient. Facial emotion recognition has not been extensively studied in groups of manic and euthymic patients compared to healthy controls. Seven manic (YMRS . 20) bipolar I and eight euthymic bipolar II disorder patients, and six healthy controls matched (1) Ekman’s Pictures of Facial Affect (EPFA) to descriptors of six basic emotions (fear, anger, surprise, disgust, sadness, happiness); (2) EPFA to one another for facial emotion; and (3) Benton Facial Recognition photographs to one another for identity. On task (1), manic patients’ scores for “fear” were lower than euthymic patients and healthy controls. Manic patients compared to controls (but not compared to euthymic patients) also had decreased scores for 4/5 (anger, surprise, disgust, and sadness, but not happiness) of the other basic emotion descriptors. Euthymic patients did not differ significantly from controls. Task (2) showed similar results, while on task (3), there were no significant between-group differences. Thus, manic patients had impaired facial fear recognition compared to both controls and euthymic bipolar II patients, and impaired facial sadness (but not happiness) recognition compared to controls. It remains to be determined whether these differences are due to the manic state or the bipolar I disorder trait. Euthymic bipolar II patients did not have facial emotion recognition deficits, in contrast to prior studies in depressed patients.

Dominance of immunoglobulin G2c in the antiphosphorylcholine response of rats infected with Trichinella spiralis.

The antibody response to the L1 stage of Trichinella spiralis has been described as biphasic. Worms resident in the intestine during the first week of infection stimulate an antibody response against a subset of larval proteins. L1 larvae in the muscle at the end stage of infection stimulate a second antibody response against tyvelose-bearing glycoproteins. Antityvelose antibodies protect rats against challenge infection with larvae. The aim of this study was to characterize the rat B-cell response against larval antigens during the intestinal phase of T. spiralis infection and to test the antiparasitic effects of such antibodies. Strain PVG rats were infected orally with 500 larvae. Antibodies specific for phosphorylcholine-bearing proteins of L1 larvae first appeared in serum 9 days postinfection. Absorption experiments showed that the majority of antilarval antibodies produced in rats 16 days after infection with T. spiralis were specific for phosphorylcholine-bearing proteins. A fraction of these antibodies bound to free phosphorylcholine. Immunoglobulin G2c (IgG2c) producing cells in the mesenteric lymph node dominated this early antibody response. IgG2c is associated with T-independent immune responses in the rat; however, a comparison of athymic rats with euthymic controls suggested that only a small fraction of the phosphorylcholine-related antibody response against T. spiralis was T independent. Phosphorylcholine is a common epitope in antigens of bacteria and nematode parasites and has been shown to be a target of protective immunity in certain bacteria. A monoclonal IgG2c antibody was prepared from infected rats and shown to be specific for phosphorylcholine. Monoclonal phosphorylcholine-specific IgG2c failed to protect rats against intestinal infection with T. spiralis. Therefore, our findings do not support a role for phosphorylcholine-bearing antigens in immune defense against T. spiralis; however, the potency of the immune response induced suggests an immunomodulatory role for the lymphocytes involved.

Expression of T-cell receptor beta-chain mRNA and protein in gamma/delta T-cells from euthymic and athymic rats: implications for T-cell lineage divergence.

The relationship between α/β and γ/δ T-cell lineages was studied in rats using RT-PCR analysis of TCRβ transcripts in γ/δ T-cell hybridomas and an intracellular staining technique to detect TCRβ protein in primary γ/δ T-cells. We report the presence of functional TCRβ transcripts in 2/9 γ/δ T-cell hybridomas. About 15 % of peripheral γ/δ T-cells and thymocytes also express TCRβ protein, giving a minimum estimate for successful Tcrb rearrangement based on ex vivo single cell analysis. In athymic rats, γ/δ T-cells expressing intracellular β protein are present but at a lower frequency than in euthymic controls, suggesting that in the thymus, more γ/δ T-cell precursors pass through a stage where functional β rearrangement has occurred than in extrathymic sites. Analysis of TCR expression in purified transitory immature CD4-8+ (iCD8SP) thymocytes and their spontaneously developing CD4+8+ (DP) progeny showed that TCRγ mRNA is expressed in iCD8SP cells but not in their immediate DP progeny that reinitiate RAG-1 transcription and commence α/βTCR expression. We conclude that rat γ/δ T cells can separate from the α/β lineage after TCRβ expression, but not after entry into the DP compartment.

The mechanism of specific prolongation of class I-mismatched skin grafts induced by retroviral gene therapy.

In the present study, we examine the mechanism of specific hyporesponsiveness to major histocompatibility complex (MHC) class I-mismatched skin allografts induced by retrovirus-mediated gene transfer of an allogeneic class I gene into syngeneic bone marrow (BM). Using appropriate congenic recombinant mouse strains, we have mapped MHC determinants that are capable of restoring rapid rejection of Kb-bearing skin grafts. Our results indicate that either a single class I or a single class II alloantigen expressed on skin in association with Kb is able to restore the rapid rejection of Kb-mismatched skin grafts. These data suggest that third-party alloantigens expressed on skin in association with Kb abrogate hyporesponsiveness by providing T cell help. Consistent with this interpretation, spleen cells from mice reconstituted with Kb-transduced BM were unable to elicit a significant anti-Kb cytotoxic T lymphocyte response in vitro unless interleukin-2 was added to the culture medium. Skin graft survival was also analyzed on B10. AKM mice thymectomized 3-4 weeks post-reconstitution with Kb-transduced BM. Thymectomy did not result in significantly prolonged survival of B10. MBR skin grafts compared to euthymic controls, suggesting that even early after reconstitution, intrathymic deletion of Kb-reactive T cells must have been incomplete. Taken together, these data suggest that prolongation of skin allograft survival in this model is controlled at the level of T cell help.

DEVELOPMENT OF NKR-P1dim/αβTCR+ CELL IS NOT THYMIC DEPENDENT IN XENOGENEIC (RAT--&gt;MOUSE) CHIMERAS. † 924

Natural Killer (NK) cells are large granular lymphocytes capable of non-MHC restricted lysis of tumor and virally infected cells without immunological priming. Rat NK cells, identified by the NKR-P1 marker, differentiate primarily in the spleen, and are present and functional in rat-->mouse xenogeneic chimeras. An NKR-P1dim/αβTCR+ population has also been identified in these xenochimeras. NKR-P1dim/αβTCR+ cells are relatively enriched in the spleen early after BMT and are characterized as small agranular cells lacking non-MHC restricted tumor lysis and rADCC activity. Large cytoplasmic granules and normal NK function develop when these cells are cultured in IL-2 enriched medium. To determine whether development of NKR-P1dim/αβTCR+ cells is thymic dependent, we prepared xenochimeras by inoculation of untreated rat bone marrow cells (BMC) into lethally irradiated, thymectomized mice. The animals were sacrificed at 1 week intervals; splenocytes and BMC were phenotyped by flow cytometric analyses for NKR-P1, αβTCR and other T-cell surface markers. Thymectomy did not diminish xenogeneic engraftment or delay splenocyte reconstitution. Importantly, the NKR-P1dim/αβTCR+ population was clearly identified in the thymectomized animals (see figure). Repopulation kinetics of these cells paralleled euthymic controls, with cell numbers peaking at 2 wks and few detected beyond 3 wks. Three color analysis demonstrated that >99% of these cells are CD3+ and CD5+, while 82% are CD8+. This cell, whose maturation is not thymus dependent, may be a common precursor for NK and T cell lines, and may play an important role in allograft rejection in immunosuppressed hosts.

T cell and non-T cell compartments can independently determine resistance to Leishmania major.

In experimental murine cutaneous leishmaniasis caused by Leishmania major (Lm), the cellular determinants governing development of protective or exacerbative T cells are not well understood. We, therefore, attempted to determine the influence of T cell and non-T cell compartments on disease outcome. To this end, T cell chimeric mice were constructed using adult thymectomized lethally irradiated, bone marrow-reconstituted (ATXBM) animals of genetically resistant, C57BL/6, or susceptible, BALB/c, backgrounds. These hosts were engrafted with naive T cell populations from H-2-congenic susceptible, BALB.B6-H-2b, or resistant, C57BL/6.C-H-2d, animals, respectively. Chimeric mice were then infected with Lm, and disease outcome was monitored. BALB/c T cell chimeric mice, BALB/c ATXBM hosts given naive C57BL/6.C-H-2d T cells, resolved their infections as indicated by reductions in both lesion size and parasite numbers. Furthermore, the mice developed typical Th1 (interferon[IFN]-gamma hiinterleukin[IL]-4lo) cytokine patterns. In contrast, both sham chimeric, BALB/c ATXBM hosts given naive BALB/c T cells, and control irradiated euthymic mice succumbed to infection, producing Th2 profiles (IFN-gamma loIL-4hiIL-10hi). C57BL/6 T cell chimeras, C57BL/6 ATXBM hosts given naive BALB.B6-H-2b T cells, resolved their infections as did C57BL/6 sham chimeras and euthymic controls. Interestingly, whereas C57BL/6 control animals produced Th1 cytokines, chimeric animals progressed from Th0 (IFN-gamma hiIL-4hiIL-10hi) to Th2 (IFN-gamma loIL-4hiIL-10hi) cytokine profiles as cure ensued. Both reconstitution and chimeric status of all mice were confirmed by flow cytometry. In addition, T cell receptor V beta usage of Lm-specific blasts was determined. In all cases, V beta use was multiclonal, involving primarily V beta 2, 4, 6, 8.1, 8.2, 8.3, 10, and 14, with relative V beta frequencies differing between H-2b and H-2d animals. Most importantly, however, these differences did not segregate between cure and noncure outcomes. These findings indicate that: (a) genetic traits determining cure in Lm infection can direct disease outcome from both T cell and non-T cell compartments; (b) the presence of the curing genotype in only one compartment is sufficient to confer cure; (c) curing genotype T cells autonomously assume a Th1 cytokine profile-mediating cure; (d) noncuring genotype T cells can mediate cure in a curing environment, despite the onset of Th2 cytokine production; and lastly, (e) antigen specificity of responding T cells, as assessed by V beta T cell receptor diversity, is not a critical determinant of disease outcome.