Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial

Some evidence suggests that the pathophysiology of schizophrenia is associated with the abnormal immune system, and cytokines may be important in schizophrenia. Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib reduce the production of proinflammatory cytokines including Th1-like cytokines. Indeed, COX-2 inhibitors rebalance type-1 and type-2 immune response. The purpose of the present investigation was to assess the efficacy of celecoxib as an adjuvant agent in the treatment of chronic schizophrenia in an eight-week, double-blind and placebo-controlled trial. Eligible participants in this study were 60 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for schizophrenia. Patients were allocated in a random fashion, 30 to risperidone 6 mg/day plus celecoxib 400 mg/day (200 mg bid) (morning and evening) and 30 to risperidone 6 mg/day plus placebo. Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the celecoxib group over the trial. However, the differences were not significant. The results of this study suggest that celecoxib may be an effective adjuvant agent in the management of patients with chronic schizophrenia and anti-inflammatory therapies should be further investigated.     

Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia

OBJECTIVE: Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. METHOD: In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. RESULTS: Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. CONCLUSIONS: Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.     

Effect of Probiotic Adjuvant Therapy on Improvement of Clinical Symptoms & Interleukin 6 Levels in Patients With Schizophrenia

Objective This study aims to examine the effect of giving probiotic adjuvant therapy on improving clinical symptoms & IL-6 levels in patients with schizophrenia. Methods This research was a double-blind, placebo-controlled trial conducted at Dadi Psychiatric Hospital, South Sulawesi Province, Indonesia in November–December 2021. The sample of the research was patients with schizophrenia undergoing hospitalization who received therapeutic doses of risperidone with a total of 21 samples in each treatment and control group. Research subjects were measured with Positive and Negative Syndrome Scale (PANSS) at baseline, 2nd, 4th, and 6th weeks. The treatment group received one capsule/12 hours/oral of probiotics for six weeks and the control group received 1 capsule/12 hours/oral placebo for 6 weeks. In addition, two measurements of IL-6 using enzyme-linked immunosorbent assay were performed in both groups, namely at the beginning of week 0 and the end of the 6th week. Results We found the decrease in the PANSS value which described the improvement in clinical symptoms of the schizophrenic group after receiving therapeutic doses of antipsychotics and probiotic capsules or the treatment group as well as the schizophrenia group receiving therapeutic doses of antipsychotics and placebo capsules or the control group. Conclusion Improvements in clinical symptoms and decreased levels of IL-6 in the group of patients with schizophrenia who received risperidone with probiotic adjuvant therapy were better than in the group of patients with schizophrenia who received risperidone without probiotics as adjuvant therapy.     

Elevated Ley antigen expression on T-lymphocytes in schizophrenic patients

Summary Le^y is a carbohydrate determinant of membrane glycoconjugates and is expressed in some tumor and embryonic cells. On T lymphocytes, it is known that human immunodeficiency virus (HIV)-infected human lymphocyte T-cell lines express elevated Le^y antigen and AIDS patients show the highest Le^y expression in T lymphocytes at lower CD4/CD8 ratio. Later, a comparative elevation of Le^y expression on T-cell subsets has been noticed to be mainly present in patients with viral diseases, such as acute and chronic hepatitis, implying an association of the highest Le^y expression with viral infection. We found that Le^y antigen was most expressed in both CD4⁺ and CD8⁺ subsets of peripheral T lymphocytes in hospitalized schizophrenic patients. On the other hand, atypical lymphocytes with stimulated morphology are known to appear in the blood circulation of schizophrenic patients. Similar atypical lymphocytes have also been described in viral and autoimmune diseases. Two possibilities have been discussed: viral association in the pathology in some schizophrenic patients; and immunological abnormalities including environmental effects under hospitalization on immune status, since normal controls (staff in psychiatric hospitals) showed higher Le^y expression than normal controls under non-psychiatric circumstances.     

Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia

BACKGROUND: Many studies have indicated that immune cytokines may be involved in the pathophysiology of schizophrenia. Recently, there have been reports that typical and atypical antipsychotic drugs may influence the levels of cytokines or cytokine receptors. The aim of this study was to compare the effect of typical and atypical antipsychotic drugs on serum interleukin-2 (IL-2), interleukin-6 (IL-6), and interleukin-8 (IL-8) and to investigate the relationship between the changes in cytokines and the therapeutic outcome in schizophrenia. METHOD: From April 1996 to August 1997, seventy-eight inpatients with a diagnosis of chronic schizophrenia (DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Serum IL-2 was assayed by radioimmunometric assay, and serum IL-6 and IL-8 concentrations were measured by quantitative enzyme-linked immunosorbent assay in patients and 30 sex- and age-matched normal subjects. RESULTS: Both risperidone and haloperidol reduced the elevated serum IL-2 concentrations in schizophrenia, and no significant difference was noted in the reduction of serum IL-2 concentrations between risperidone and haloperidol treatment. Neither risperidone nor haloperidol showed significant influence on the higher serum IL-6 or IL-8 concentrations in schizophrenia. Correlations between serum IL-2 or IL-8 concentrations at baseline and the therapeutic outcome were observed, demonstrating that patients presenting with low concentrations of serum IL-2 or IL-8 at baseline showed greater improvement and patients presenting with higher serum IL-2 or IL-8 concentrations at baseline showed less improvement after treatment. CONCLUSIONS: Both typical and atypical anti-psychotic drugs may at least partially normalize abnormal immune alterations in schizophrenia. Some immune parameters at baseline may be useful for predicting the neuroleptic response of schizophrenic patients.     

Effect of risperidone on serum cytokines

A variety of cytokines are dysregulated in schizophrenia, and some antipsychotic drugs effect cytokines. In order to examine the effect of risperidone on plasma cytokines, we measured the serum level of IL-1b, IL-2, IL-6, IL-12, and INF-g during acute states of illness, and after 4 weeks of treatment with risperidone in 19 schizophrenic patients. The patients' psychopathology was assessed by PANSS. Plasma IL-12 levels increased significantly after 4 weeks of treatment (p = .002). Plasma IL-b, IL-2, IL-6, and INF-g levels were not significantly different before and after treatment. There were no significant correlations between the changes in cytokine levels and the changes in PANSS scores. Increased IL-12 may contribute to activation of immune responses during treatment with risperidone. IL-12 may play an important role in immune responses related to neuropsychiatry.     

Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients

In an attempt to define potential immunological dysfunctions in schizophrenia, we determined the production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon- (IFN-), and soluble IL-2 receptor (sIL-2R) in a whole-blood assay after stimulation with phytohemagglutinin (PHA) as well as the serum concentrations of sIL-2R. Because CD₄ ⁺CD45RO⁺T cells are the main producers of IFN-, we determined the percentage of these cells, as well as of pan T, CD4⁺T, and CD8⁺T cells, by flow cytometry. A whole-blood count was performed in addition. Two groups of patients were examined, paranoid-type and residual-type schizophrenics. The numbers of both monocytes and neutrophils, but not of lymphocytes, were increased significantly in the schizophrenic sample. The IFN- production of the schizophrenics as a whole group, and of the paranoid patients, was reduced significantly in comparison with the control group (p0.05). The residual patients produced less IFN- than the controls, but more than the paranoid patients. The latter differences did not reach statistical significance. The production of IL-4, which physiologically antagonizes the production of IFN-, was not significantly higher in the patient group. No changes in the lymphocyte subpopulations were observed. The production of IL-2 showed a trend toward reduction in paranoid patients, but not in residual schizophrenics. The serum sIL-2R levels were elevated slightly in schizophrenics when compared with controls. In order to rule out a possible effect of cortisol on cytokine production, 20 schizophrenic were compared with 20 age- and gendermatched controls. However, neither elevated cortisol levels were detected in the schizophrenic sample, nor significant intercorrelations between cortisol levels and cytokine production, or levels of sIL-2R, respectively. In summary, our data reinforce the possibility of immune dysfunction in schizophrenia and point to the possible relevance of disease subgroups in this respect.     

Changes of percentages in immune cells phenotypes and cytokines production during two-year IFN-β-1a treatment in multiple sclerosis patients

Abstract. Objective: The aim of the study was to find out whether INF--1a influences the immune profile of peripheral blood (PB) leukocytes in MS patients. Method: We have studied 20 patients with relapsing-remitting form of MS treated with INF--1a using twocolor cytometry. We determined immune cells phenotypes and production of some cytokines: IL-4, IL-10, IL-12, IFN-, before drug administration and after starting the treatment. Results: In MS patients an increased percentage of CD14⁺CD86⁺ cells and CD3⁺CD25⁺ cells was noticed after 6, 9 and 12 months of INF--1a therapy. Among cytokine-producing cells we noted an increased fraction of CD3⁺IL-4, CD14⁺IL-10 and CD14⁺IL-12 cells after 12 months, which decreased to the level observed before treatment after 24-month therapy. Conclusions: IFN--1a treatment was associated with significant changes in immune response. This effect was mostly evident within the first year of treatment.     

Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor

There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment.     

利培酮合并赛来昔布治疗对精神分裂症首次发病患者认知功能的影响

目的 探讨利培酮合并赛来昔布对精神分裂症首发患者认知功能的影响.方法 符合美国精神障碍诊断与统计手册第4版诊断标准的精神分裂症首次发病(以下简称首发)住院患者90例,随机分到利培酮+赛来昔布组(研究组,46例)或利培酮+空白剂组(对照组,44例),观察治疗时间均为12周.认知功能评定使用阳性和阴性症状量表、汉密尔顿抑郁量表、威斯康星卡片分类(WCST)、重复性神经心理测查系统(RBANS).结果 治疗第12周末,研究组PANSS总分及分量表分低于对照组(P均＜0.05);研究组HAMD评分低于对照组;两组患者RBANS测验总分及部分分量表评分均较基线明显提高,差异均有统计学意义(P均＜0.05);WCST部分因子分均较基线有明显改善,差异均有统计学意义(P均＜0.05);两组间各量表评分的差异均无统计学意义(P均＞0.05).研究组男性患者的延时记忆量表分明显高于女性患者,差异有统计学意义(F=4.8;υ=1.0,38;P=0.03),且临床症状的改善与认知功能的提高存在显著相关性(P＜0.05).结论 利培酮具有改善首发精神分裂症患者认知功能的作用;赛来昔布对男性患者的延时记忆有改善作用.     

Human CD8(+) T cells and NK cells express and secrete S100B upon stimulation

Previous studies have demonstrated the utility of S100B as a surrogate marker of brain-related pathologies, e.g. neuropsychiatric disorders, and melanoma progression, which have an inflammatory component. This study addresses the relevance of S100B⁺ lymphocytes in mediating such responses. S100B expression was determined in human peripheral blood leukocytes isolated from healthy volunteers using flow cytometry. S100B⁺ lymphocytes were characterised for phenotype, cytokine production and S100B secretion. In addition, we investigated whether S100B activates monocytes and neutrophils.S100B⁺ cells comprised 2-4% of all lymphocytes and the majority displayed a CD3⁺ CD8⁺ phenotype; fewer cells were CD3⁻ CD56⁺ NK lymphocytes. Comparison of S100B⁺ and S100B⁻ CD3⁺ CD8⁺ cells revealed no differences in production of interferon gamma (IFNγ) and interleukin-2 (IL-2). Stimulation of S100B⁺ CD3⁺ CD8⁺ lymphocytes with anti-CD3 or phytohaemagglutinin resulted in release of S100B. High concentrations of recombinant human S100B triggered upregulation of CD11b and membrane shedding of CD62L in granulocytes and monocytes.These findings set the stage for a new field of research addressing a S100B-mediated crosstalk between the innate and adaptive immune systems if close proximity of effector and responder cells accomplishes sufficient local S100B levels. In various physiological and pathological conditions S100B might function as an interface to immunological processes, distinct from known cytokine- and chemokine-mediated pathways.     

Cellular and Humoral Immune System in Schizophrenia: A Conceptual Re-Evaluation

Summary: Immune alterations in schizophrenia have been described for decades. However, modern immunological methods and new insights into the highly developed and functionally differentiated immune system allow an integrative view of both the older and also more recent findings of immunological abnormalities in schizophrenia. The conceptual advances in immunology require the re-evaluation of elder immunological findings in schizophrenia. In this overview, recent advances in immunological research regarding the differentiation between T-Helper-1 and T-Helper-2 cells and between the socalled specific and unspecific arms of the immune system are discussed. The unspecific “innate” immune system shows signs of an over-activation in unmedicated schizophrenic patients, as increased monocytes and γδ-cetls point to. Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of monocytes/macrophages, too. In contrast, several parameters of the specific cellular immune system are blunted, e.g. the decreased T-helper-1 (TH-1) related immune parameters in schizophrenic patients, both in vitro and in vivo. It seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with schizophrenia. During therapy with antipsychotics, the specific TH-1 related immune answer becomes activated, but the B-cell system and the antibody production become activated too.     

米诺环素辅助治疗精神分裂症阴性症状的效果及对免疫因子的影响

目的探讨米诺环素辅助治疗精神分裂症阴性症状的效果及免疫学机制。方法将92例符合美国《精神疾病诊断与统计手册(第4版)》(DSM-IV)诊断标准、以阴性症状为主且单一利培酮治疗的精神分裂症患者随机分为米诺环素组(n=46)或安慰剂对照组(n=46),治疗周期为16周。于入组及出组时以阴性症状评定量表(SANS)、阳性和阴性症状量表(PANSS)评定疗效,测定治疗前后白介素1-β(IL-1β)、肿瘤坏死因子-α(TNF-α)、一氧化氮(NO)浓度变化。结果 PANSS阴性症状评分和总评分与安慰剂组相比,减分差异有统计学意义(P0.01);两组治疗前后除NO外其余两个因子的浓度变化均无统计学意义(P0.05)。结论米诺环素辅助治疗精神分裂症的阴性症状有效,但作用机制仍不明,是否通过抑制NO浓度的变化尚需进一步的研究。     

Regulatory T cells increased while IL-1β decreased during antidepressant therapy

Background

Regulatory T cells (Tregs, CD4⁺CD25^hi) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1β, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4⁺CD25^hi Tregs in these immunological processes during antidepressant therapy.

Methods

16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctor’s choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1β, and measured IL-1β, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4⁺CD25^hi Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21).

Results

HAMD-21 score, IL-1β serum levels as well as LPS-stimulated IL-1β and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4⁺CD25^hi cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed.

Conclusions

The increase in CD4⁺CD25^hi Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.     

Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients

The adaptive immune response of ovarian cancer patients has been linked to survival, and is known to be impaired in the tumor microenvironment. Little is known about relationships between biobehavioral factors such as depressed mood and anxiety and the adaptive immune response in ovarian cancer. Thirty-seven patients with epithelial ovarian cancer and 14 patients with benign ovarian neoplasms completed psychosocial questionnaires pre-surgery. Lymphocytes from peripheral blood, tumor, and ascites (fluid around the tumor), were obtained on the day of surgery. Expression of the Type-1 cytokine interferon-gamma (IFNγ), and the Type-2 cytokine interleukin-4 (IL-4) by T-helper (CD4⁺) and T-cytotoxic (CD8⁺) cells was measured under autologous tumor-stimulated, polyclonally-stimulated, or unstimulated conditions. Links with mood were examined. Among cancer patients, marked elevations in unstimulated and tumor-stimulated Type-2 responses were seen, particularly in ascites and tumor-infiltrating lymphocytes (P values < 0.01). With polyclonal stimulation, lymphocytes from all compartments expressed elevated Type-1 cytokines (P values < 0.014). Depressed and anxious mood were both associated with significantly lower ratios of polyclonally-stimulated CD4⁺ cells producing IFNγ (TH₁ cells) vs. IL-4 (TH₂ cells) in all compartments (depressed mood: P = 0.012; anxiety: P = 0.038) and depressed mood was also related to lower ratios of polyclonally-stimulated CD8⁺ cells producing IFNγ (TC₁) vs. IL-4 (TC₂) (P = 0.035). Although effects of polyclonal stimulation should be generalized with caution to the in vivo immune response, findings suggest that depressed and anxious mood are associated with greater impairment of adaptive immunity in peripheral blood and in the tumor microenvironment among ovarian cancer patients.     

T-cells and psychopathology in schizophrenia: relationship to the outcome of neuroleptic therapy

Until recently, attention has been focused on the pathogenetic aspects of immunological findings in schizophrenic patients. There has been no mention of the relationship between such findings and schizophrenic symptoms. To study the probable relationship between T-cells and T-cell subgroups in the course and prognosis of schizophrenia, immunological and psychopathological parameters were correlated in 55 patients suffering from schizophrenia (ICD-9: 295.0–295.6) or schizoaffective psychosis (ICD-9: 257.7) before neuroleptic treatment. The correlations were performed for a second time in 24 of these patients after clinical improvement at a reinvestigation. Positive correlations of the Brief Psychiatric Rating Scale and the Scale for Assessment of Negative Symptoms with the numbers of CD3⁺ and CD4^- T-cells (total T- and T-helper cells), which were enhanced compared with controls, were found at the reinvestigation after clinical improvement, whereas no significant correlation could be detected at the pretreatment investigation. These results show that the cellular immune parameters are related to the course of the psychopathological symptoms in schizophrenia and, possibly, are a marker of the therapeutic outcome of neuroleptic treatment.     

Activated suppressor cell function in multiple sclerosis — clinical correlations

Activated suppressor cell function mediated by either freshly isolated peripheral blood mononuclear cells (MNCs), freshly isolated CD8⁺ lymphocytes or by CD8⁺ cell lines, has previously been found to be reduced compared to controls in multiple sclerosis (MS) patients with progressive disease (MS-P). In this study, we found that suppressor activity mediated by CD8⁺ cell lines, derived from MS patients with stable disease (MS-S) patients and maintained in culture for 14 days, was significantly greater (45 ± 6%) compared to that mediated by MS-P patients' CD8⁺ cells (11 ± 4%, P < 0.005). The MS-S suppressor values were, however, suggestively reduced compared to controls (60 ± 6%, P < 0.05). MNC-mediated suppressor values for the MS-S group (61 ± 5%) did not differ from the control group (67 ± 6%). Values for the MS-P group (7 ± 6%) were significantly reduced compared to MS-S and control groups. Cytotoxic activity mediated by CD8⁺ cell lines showing defective suppressor function did not differ from control values. The cell lines in MS and control did not differ with respect to their rate of proliferation in the presence of IL-2 and OKT3. Suppressor function in this assay was ablated if exogenous IL-2 was removed from the culture media. These data suggest that defective activated suppressor function is characteristic of the progressive form of MS, although a suppressor defect is also partially expressed in stable MS patients when CD8⁺ cell lines are studied.     

Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4⁺ count was 117 and the HIV viral load >10⁴; imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4⁺ was 300 and HIV viral load <10³, but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8⁺ lymphocytes; CD4⁺ lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8⁺/CD4⁺ T cells, with massive infiltration of the cerebral parenchyma by CD8⁺ cytotoxic T lymphocytes in the absence of sufficient CD4⁺ response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.     

Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia

There are a number of indications that schizophrenia is associated with changes in the immune system. Although functional studies have mostly demonstrated decreased in vitro production of IL-2 by peripheral blood mononuclear cells (PBMCs) stimulated with mitogen, the reason is unclear. The aim of the study was to explore the relationship between IL-2 production and CD4+ cells which mainly secret IL-2 in non-Caucasian patients with schizophrenia. Blood CD4+ cells and mitogen-stimulated IL-2 secreting cells identified by an immunohistochemical study with the alkaline phosphatase/anti-alkaline phosphatase (APAAP) technique, and in vitro IL-2 production with radioimmunometric assay (RIA) were measured in 30 schizophrenic patients and 30 normal control subjects matched for sex, age and race. The results showed that blood CD4+ cells and mitogen-induced IL-2 secreting cells and IL-2 production were significantly lower in schizophrenic subjects than in the normal controls. There was significantly positive correlation between CD4+ cells and IL-2 production in normal controls but not in patients. These findings suggest that immune disturbance may be present in schizophrenic patients. The lower in vitro IL-2 production is probably related to the decreased number of T-cells that secret IL-2, as well as to the intrinsic disorder of the patients' T cells.