Reduced Natural Killer Activity Research Articles

Delayed NK Cell Reconstitution and Reduced NK Activity Increased the Risks of CMV Disease in Allogeneic-Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) infection has a significant impact in patients after allogeneic hematopoietic stem cell transplantation (HSCT). We investigated natural killer (NK) cell reconstitution and cytotoxic/cytokine production in controlling CMV infection, especially severe CMV disease in HSCT patients. Fifty-eight patients with acute myeloid leukemia (AML) who received allo-HSCT were included. We monitored NK reconstitution and NK function at baseline, 30, 60, 90, 120, 150, and 180 days after HSCT, and compared the results in recipients stratified on post-HSCT CMV reactivation (n = 23), non-reactivation (n = 24) versus CMV disease (n = 11) groups. The CMV disease group had a significantly delayed recovery of CD56dim NK cells and expansion of FcRγ-CD3ζ+NK cells started post-HSCT 150 days. Sequential results of NK cytotoxicity, NK cell-mediated antibody-dependent cellular cytotoxicity (NK-ADCC), and NK-Interferon-gamma (NK-IFNγ) production for 180 days demonstrated delayed recovery and decreased levels in the CMV disease group compared with the other groups. The results within 1 month after CMV viremia also showed a significant decrease in NK function in the CMV disease group compared to the CMV reactivation group. It suggests that NK cells’ maturation and cytotoxic/IFNγ production contributes to CMV protection, thereby revealing the NK phenotype and functional NK monitoring as a biomarker for CMV risk prediction, especially CMV disease.

Effect of kumquat (Fortunella crassifolia) pericarp on natural killer cell activity in vitro and in vivo.

Natural killer (NK) cells play a key role in innate immune defense against infectious disease and cancer. A reduction of NK activity is likely to be associated with increased risk of these types of disease. In this study, we investigate the activation potential of kumquat pericarp acetone fraction (KP-AF) on NK cells. It is shown to significantly increase IFN-γ production and NK cytotoxic activity in human KHYG-1 NK cells. Moreover, oral administration of KP-AF significantly improves both suppressed plasma IFN-γ levels and NK cytotoxic activity per splenocyte in restraint-stressed mice. These results indicate that raw kumquat pericarp activates NK cells in vitro and in vivo. To identify the active constituents, we also examined IFN-γ production on KHYG-1 cells by the predicted active components. Only β-cryptoxanthin increased IFN-γ production, suggesting that NK cell activation effects of KP-AF may be caused by carotenoids such as β-cryptoxanthin.

Reduced IL‐10 production contributes to impaired NK cytotoxicity in old mice fed a high folic acid diet (638.3)

Natural killer (NK) cells are important for immunity against malignant and virally infected cells. High folic acid intake, which may be linked with higher risk of colon cancer, was associated with lower NK activity in older women. To study the underlying mechanisms, we created a mouse model and found that aged mice fed a high folic acid (HFA) diet had reduced NK activity. In this study, we determined if expression of cytokines that are known to activate NK activity (IL‐10, IFN‐γ, TNF‐α) are affected by a HFA diet in aged mice.Female C57BL/6 mice (16 mo) were fed a control (1x RDA folic acid) or a HFA diet (20x RDA folic acid) for 3 months. Splenocytes were collected and stimulated with LPS for 24 h for ex vivo production of IL‐10, IFN‐γ, and TNF‐α determined by cytometric bead array.In HFA mice, IL‐10 production was 50.7% less than that of the control mice (P=0.028) but no differences were found in IFN‐γ and TNF‐α production. Since IL‐10 activates NK cells, we examined whether addition of IL‐10 to the splenocyte cultures would restore NK activity in the HFA group. We found that NK activity increased for both groups (P<0.01), but the HFA group had larger percent increase in NK activity as compared to control mice (P=0.058). These results indicate that IL‐10 restored the lower NK activity in aged mice fed a HFA diet.These findings suggest the decreased NK activity due to a high folic acid diet may in part be due to impaired IL‐10 secretion.Grant Funding Source: Supported by USDA contract # 51520‐008‐045 and HNRCA Pilot grant

Participation of natural killer cells in the pathogenesis of bile duct lesions in biliary atresia

AimsImmunological disturbances including innate immunity after a suspected viral infection are considered important to the pathogenesis of bile duct lesions in cases of biliary atresia (BA). In this study, we...

Cytokine‐induced Suppression of Medial Preoptic Neurons

We have shown that the medial preoptic area (MPO) in the hypothalamus is a major site where interferon (IFN)-alpha acts to induce suppression of splenic natural killer (NK) cell activity through an activation of sympathetic nervous system (SNS) in rats. Here, we discuss the hypothalamic mechanisms of the cytokine action using in vivo and in vitro preparations in rats. Lesion of the MPO activated the SNS and suppressed splenic NK cell activity in anesthetized rats, suggesting that the MPO had an inhibitory influence on nerve activity. Since both IFN-alpha and interleukin (IL)-1beta are known to suppress MPO neuron activity, it is suggested that the suppression/loss of the MPO caused by cytokine actions/lesions disinhibits the hypothalamic-sympathetic pathway, thereby resulting in an increase in the splenic SNS and reduction of NK activity. To explore the cellular mechanisms of the suppression of MPO neurons, the effects of Prostaglandin E2 (PGE2), one of the major mediators of cytokine action in the brain, on the glutamate-induced membrane currents were examined using the perforated patch-clamp method in mechanically dissociated MPO neurons. Patch-clamp analysis revealed that PGE2 potentiated the Ca2+-dependent K+ current (KCa) stimulated by Ca2+ entry through N-methyl-D-aspartate channels. We suggest that the cytokine-induced decrease in the firing rates of MPO neurons may be a result of an increase in interspike intervals caused by PGE(2)-induced enhancement of KCa in the presence of glutamatergic inputs.

Loss of natural killer activity as an indicator of relapse in acute leukaemia

A role for naturally occurring cytotoxic cells in immunosurveillance against malignancy has been presumed in several studies. The natural killer activity (NKA) of peripheral blood mononuclear cells was therefore measured at regular intervals in patients with acute leukaemia and expressed specific cytotoxicity. Sixty controls had a median NKA of 33.6% (range 15.4-71). Seventy-three patients with acute lymphoblastic leukaemia (ALL) and acute non-lymphoblastic leukaemia (ANLL) with untreated or relapsed disease had a median activity of 2.4% (range 0-13.4) (P less than 0.001), while 57 patients who had achieved complete remission had a median activity of 22.7% (range 9.5-64.4). In 15 patients, reductions of NKA were seen prior to 16 episodes of relapse. In ten of these (nine with ANLL and one with ALL), 11 relapses were preceded within 10 weeks by drops in NKA to less than 30% of remission levels. The median NKA of the group prior to the drop in activity was 25.5% and the median first low value was 6.0%. Five patients who relapsed after allogeneic bone marrow transplantation had significant, sustained drops in NKA, 5-9 weeks earlier. The median NKA prior to the drop was 25.6% and the median first low value was 8.0%. We therefore conclude that there was a marked reduction in NKA in patients with active acute leukaemia when compared with healthy blood donors and that this activity substantially improved in complete remission. All patients who relapsed had significantly reduced NKA which in some, significantly preceded the time of relapse. These data suggest that the regular assessment of NKA in patients with acute leukaemia may be a useful diagnostic tool.

Reduced NK activity correlates with active disease in HIV- patients with multidrug-resistant pulmonary tuberculosis.

There has been a global increase in the incidence of multidrug-resistant pulmonary tuberculosis (TB). As there are no previous reports of immune function in HIV- patients with multidrug-resistant pulmonary TB, a comprehensive assessment of cellular immunity in this setting was undertaken. This involved a prospective, case-controlled study which included five patients with active multidrug-resistant pulmonary TB and five matched controls with active non-resistant infection, and documented the changes in immune parameters which occurred upon clinical resolution. Patients with multidrug-resistant TB had significantly lower fresh natural killer (NK) cell activity than matched controls with non-resistant pulmonary TB (P < 0.05). This was a specific abnormality, as there were no significant differences in antigen-specific cytotoxicity or lymphocyte proliferation in the case-controlled study. Follow-up assessment of the patients with multidrug-resistant infections indicated that clinical improvement correlated with a moderate increase in NK cell activity. Impaired NK cell function may be involved in the pathogenesis of multidrug-resistant TB.

Natural Killer Cells in Hepatitis C Virus Infection: From Innate Immunity to Adaptive Immunity

Natural killer (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is up-regulated on NK cells in patients with chronic hepatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as in nontransformed hepatocytes, but not in K562 cells, a classic NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing interferon-gamma in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness toward K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which were restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity toward HCV-infected or transformed cells in chronic hepatitis C.

Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures.

Postoperative immunosuppression is partly ascribed to anesthesia and has been suggested to compromise patients' resistance to infection and tumor metastasis. We compared the effects of various anesthetics on natural killer (NK) cell activity and on resistance to experimental metastasis, and studied mediating mechanisms and prophylactic measures. Fischer 344 rats served as controls or were anesthetized for 1 h with ketamine, thiopental, halothane, or propofol. Anesthetized rats were either maintained in normothermia or left to spontaneously reach 33 degrees C-35 degrees C. Rats were then injected IV with MADB106 tumor cells, and 24 h later lung tumor retention was assessed, or 3 wk later, lung metastases were counted. Additionally, the number and activity of circulating NK cells were assessed after anesthesia. All anesthetics, except propofol, significantly reduced NK activity and increased MADB106 lung tumor retention or lung metastases. Hypothermia had no significant effects. Ketamine increased metastasis most potently, and this effect was markedly reduced in rats pretreated with a beta-adrenergic antagonist (nadolol) or with chronic small doses of an immunostimulator (polyriboinosinic:polyribocytidylic acid). Overall, the marked variation in the NK-suppressive effects of anesthetics seems to underlie their differential promotion of MADB106 metastasis. Prophylactic measures may include perioperative immunostimulation and the use of beta-blockers. This study in a rat model of pulmonary metastasis demonstrates that some anesthetics, but not others, increase susceptibility to tumor metastasis, apparently by suppressing natural killer cell activity. Ketamine was most deleterious, and its effects were prevented by peripheral blockade of beta-adrenoceptors combined with low levels of immunostimulation.

Reduced NK activity in pulmonary tuberculosis patients with/without HIV infection: identifying the defective stage and studying the effect of interleukins on NK activity

Setting: A study was undertaken to understand the non-major histocompatibility restricted cytotoxicity in order to delineate the role of natural killer (NK) cells towards the development of host immunity to tuberculosis.Objective: (a) Enumeration of NK cell numbers and activity in normal individuals (35), pulmonary tuberculosis patients (32), HIV-infected TB patients (20) and patient contacts (10), (b) effect of treatment on NK status, (c) enumeration of effector-target conjugates and (d) effect of in vitro cytokine stimulation on NK activity.Design: NK cells were enumerated by flowcytometry. NK activity was assessed by chromium release assay before and after treatment for tuberculosis and after stimulation with IL-2/IL-12. Novel flow cytometric method was standardized to enumerate effector-–target conjugates.Results: No changes were seen between different groups as far as number of NK cells and relative proportions of different conjugate types were concerned, but there was a decrease in NK activity in TB patients which increased after treatment. Augmentation of NK activity was observed after cytokine stimulation.Conclusion: Lowered NK activity during tuberculosis infection is probably the ‘effect’ and not the ‘cause’ for the disease as demonstrated by the follow-up study. Similar number of conjugates in both groups indicates no defect in the recognition/binding step but probably at subsequent steps of the cytotoxic process. Augmentation of NK activity with cytokines implicates them as potential adjuncts to tuberculosis chemotherapy.

Comparison of the effects of dopaminergic and serotonergic activity in the CNS on the activity of the immune system

This work demonstrates that the natural killing function of the innate immune system is affected in psychiatric disorders related primarily to serotonergic pathways in the CNS rather than to psychiatric disorders which involve mainly dopaminergic pathways. Only depressive patients demonstrated low natural killer (NK) cell activity, which is inversely correlated to the intensity of depression and could be reversed by serotonin selective re-uptake inhibitors concomitant with clinical improvement. This phenomenon is absent in Parkinson's and schizophrenic patients, in whom no reduction in NK activity was observed. Also, no effect on NK activity could be demonstrated following the specific respective treatments by dopamine (D 2) blockers or agonists.

The role of gamma/delta T-cell receptor-positive cells in pregnancy: part II.

We have previously demonstrated a significantly increased ratio of gamma/delta T-cell receptor (TCR)-positive progesterone receptor(PR)-positive cells in the peripheral blood of healthy pregnant women compared to that of recurrent aborters or non-pregnant individuals. Treatment of pregnancy lymphocytes with a pan anti-gamma/delta TCR antibody inhibits progesterone-induced blocking factor (PIBF) production, increases natural killer (NK) activity, and alters the cytokine profile. The present study was aimed at investigating the role of the different gamma/delta subpopulations in these phenomena. Peripheral blood lymphocytes from healthy pregnant women were incubated with either anti-gamma1.4 and delta1, or anti-gamma9 and delta2 antibodies. The effect of these treatments on PR induction and interleukin (IL)-10 and IL-12 expression were tested by immunocytochemistry. NK activity of anti-gamma/delta treated lymphocytes was also determined. In peripheral blood of healthy pregnant women, the most frequently occurring chain combination was gamma1.4/delta1, whereas in recurrent aborters, the gamma9/delta2 combination was predominant. Treatment of normal pregnancy lymphocytes with a mixture of gamma1.4 and delta1 antibodies resulted in a significantly reduced NK activity and increased PR and IL-10 expression, whereas treatment with a mixture of gamma9 and delta2 antibodies significantly reduced IL-10 production and slightly increased IL-12 production and NK activity. These data suggest the presence of two functionally distinct subpopulations in the peripheral blood of pregnant women.

Interferon-alpha acts at the preoptic hypothalamus to reduce natural killer cytotoxicity in rats.

We previously demonstrated that an intracerebroventricular injection of recombinant human interferon-alpha (rhIFN-alpha) reduced the cytotoxicity of splenic natural killer (NK) cells in rats and mice. In the present study, we investigated the brain sites at which rhIFN-alpha acts to suppress splenic NK activity in unanesthetized rats implanted unilaterally with a chronic hypothalamic cannula. A microinjection of 200 U of rhIFN-alpha into the medial part of the preoptic hypothalamus reduced NK activity to approximately 60% of control 30 min after the injection. Administration of 50 U of rhIFN-alpha also decreased NK activity to approximately 80%. The injection of 200 U of rhIFN-alpha into other hypothalamic areas (lateral preoptic hypothalamus, ventromedial hypothalamus, lateral hypothalamus, and paraventricular nucleus) had no effect. The medial preoptic hypothalamus-rhIFN-alpha-induced immunosuppression was completely blocked by splenic denervation, but not by adrenalectomy. These results suggest that IFN-alpha suppresses splenic NK activity predominantly through the medial preoptic hypothalamus-sympathetic pathway.

Impaired natural killer cytotoxicity in peripheral blood mononuclear cells in Graves' disease.

We studied the natural killer (NK) activity of peripheral blood mononuclear cells (PBMC) in patients with Graves' disease (GD). Peripheral blood mononuclear cells from 20 untreated hyperthyroid patients with GD showed a significantly reduced NK activity against 51 Cr-labeled K562 cells (33.9 +/- 15.9%), while in 32 euthyroid patients under antithyroid drug therapy. NK activity was similar to that of controls (46.9 +/- 17.3 and 49.9 +/- 20.2%, respectively). Furthermore, normalization of thyroid function with antithyroid drugs was associated with a significant increase and normalization of NK activity during the follow-up of nine GD patients (from 29.2 +/- 17.9 to 48.1 +/- 16.5%). This phenomenon could not be ascribed to a defective number of NK cells because the amounts of CD56+ and CD16+ cells in PBMC from both hyperthyroid and euthyroid GD patients were within normal ranges. Natural killer activity of PBMC from patients with toxic multinodular goiter was similar to that of normal controls (45 +/- 12.8 to 49.9 +/- 20%). No correlation was found between natural killer activity and serum levels of free thyroxine, TSH-inhibitory immunoglobulins, thyroidal antibodies to thryoglobulin and thyroidal microsomal antigen, dose or duration of antithyroid drug therapy. Natural killer activity from both controls and GD patients was enhanced in vitro by addition of recombinant interleukin 2 (IL-2), reaching control levels in hyperthyroid patients. These abnormalities were not associated with a defective IL-2 production by T cells, nor with a decreased IL-2R expression. We conclude that in untreated Graves' disease there is a decrease in NK cell activity in PBMC, probably dependent on the autoimmune process.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody-independent protection in mice against type Ia group B streptococcus lethal infection.

There is ample evidence that protection against group B streptococcal (GBS) disease, both in experimental animals and in humans, is related to the presence of specific antibodies and complement. However, until now the possibility of increasing resistance to GBS infection by potentiating natural cell-mediated immunity in the host, has not been explored. In this study we examine the effect of administering in vivo MVE-2 (a polymer fraction of 1,2-co-polymer of divinyl ether and maleic anhydride) and inactivated Candida albicans (CA) cells on mouse resistance to the reference strain type Ia 090 GBS (GBS-090) lethal infection. MVE-2 and CA, respectively a synthetic and a microbial biological response modifier (BRM), are strong inducers and activators of natural resistance effectors, such as natural killer (NK) cells, macrophages and polymorphonuclear cells (PMN). The results showed that MVE-2 protected 100% CD-1 mice from a systemic lethal challenge with GBS-090 (5 x 10(3) microorganisms/mouse) when administered 3 days before infection at dose of 50 mg kg-1. CA treatment, in five doses (CA-5d) over 14 days protected 100% mice when administered at 2 x 10(7) cells/mouse and when the last CA injection was given 1 day before the GBS-090 challenge. Instead, when the GBS-090 challenge was performed by intraperitoneal route, protection was obtained with CA-5d treatment but not with MVE-2. The possibility that MVE-2 or CA stimulated a rapid production of specific antibodies against GBS-090 infection was excluded by the ELISA assay. Evidence exists that NK cells do not play a primary role as effectors in the MVE-2 and CA conferred protection since the strong reduction in NK activity, due to in vivo administration of anti-asialo GM1 antibodies before GBS-090 infection, did not influence the BRM-induced protection. Besides, high NK activity levels, induced by in vivo rhIL-2 administration, did not protect the mice against GBS-090 infection. Both studies on in vivo clearance and in vitro microbicidal activity, showed that, after 1 h, immunopotentiated effectors were unable to kill GBS-090, but were highly effective against GBS type VI. These results seem to indicate that intracellular GBS-090 killing is a slow process requiring more than 1 h. This study demonstrates that it is possible to increase resistance to GBS-090 lethal infection by BRMs, by potentiating the antibody-independent microbicidal activity of the phagocytes.

Antibody-independent protection in mice against type Ia group B streptococcus lethal infection

There is ample evidence that protection against group B streptococcal (GBS) disease, both in experimental animals and in humans, is related to the presence of specific antibodies and complement. However, until now the possibility of increasing resistance to GBS infection by potentiating natural cell-mediated immunity in the host, has not been explored. In this study we examine the effect of administering in vivo MVE-2 (a polymer fraction of 1,2-co-polymer of divinyl ether and maleic anhydride) and inactivated Candida albicans (CA) cells on mouse resistance to the reference strain type Ia 090 GBS (GBS-090) lethal infection. MVE-2 and CA, respctively a synthetic and a microbial biological response modifier (BRM), are strong inducers and activators of natural resistance effectors, such as natural killer (NK) cells, macrophages and polymorphonuclear cells (PMN). The results showed that MVE-2 protected 100% CD-1 mice from a systemic lethal challenge with GBS-090 (5 × 103 microorganisms/mouse) when administered 3 days before infection at dose of 50 mg kg−1. CA treatment, in five doses (CA-5d) over 14 days protected 100% mice when administered at 2 × 107 cells/mouse and when the last CA injection was given 1 day before the GBS-090 challenge. Instead, when the GBS-090 challenge was performed by intraperitoneal route, protection was obtained with CA-5d treatment but not with MVE-2. The possibility that MVE-2 or CA stimulated a rapid production of specific antibodies against GBS 090 infectio was excluded by the ELISA assay. Evidence exists that NK cells do not play a primary role as effectors in the MVE-2 and CA conferred protection since the strong reduction in NK activity, due to in vivo administration of anti-asialo GM1 antibodies before GBS-090 infection, did not influence the BRM-induced protection. Besides, high NK activity levels, induced by in vivo rhIL-2 administration, did not protect the mice against GBS-090 infection. Both studies on in vivo clearance and in vitro microbicidal activity, showed that, after 1 h, immunopotentiated effectors were unable to kill GBS-090, but were highly effective against GBS type VI. These results seem to indicate that intracellular GBS-090 killing is a slow process requiring more than 1 h. This study demonstrates that it is possible to increase resistance to GBS-090 lethal infection by BRMS, by potentiating the antibody-independent microbicidal activity of the phagocytes.

IN VITRO ENHANCEMENT OF NATURAL KILLER CELL ACTIVITY BY BCG AND THE ANTAGONISTIC INHIBITION OF THE SUSCEPTIBILITY OF K562 CELLS TO LYSIS BY PERIPHERAL BLOOD LYMPHOCYTES IN PATIENTS WITH URINARY BLADDER TUMOR

The effect of bacillus Calmette-Guerin (BCG) on the natural killer (NK) activity of peripheral blood lymphocytes (PBL) and the susceptibility of K562 cells to lysis by PBL in patients with urinary bladder tumors (UBT) was evaluated using a 4-h 51Cr release assay. The addition of BCG 0.1-1 mg/ml to the assay increased NK activity. In contrast, BCG at higher concentrations (10 mg/ml) reduced NK activity. This effect of BCG was also observed in healthy donors. Pretreatment of PBL with BCG 0.1-1 mg/ml also resulted in increased NK activity, while higher concentrations of BCG depressed it. Treatment of K562 cells with BCG 1-10 mg/ml for 3 hours reduced their susceptibility to lysis by PBL. Kinetic studies showed that the reduced susceptibility became apparent 3 hours after initiation of culture of K562 cells with BCG and lasted 12 hours. The susceptibility of BCG-treated K562 cells to lysis by purified NK cells and lymphokine activated killer (LAK) cells was also reduced. Both live and dead BCG exerted an inhibitory effect on the target cells. The effector-to-target binding assay demonstrated that treatment with BCG reduced the number of PBL conjugates with K562 cells. These results indicate that BCG increases the NK activity of PBL, while rendering K562 cells resistant to PBL lysis by inhibiting the effector-to-target binding. BCG at lower concentrations (0.1-1 mg/ml) may be useful in patients with UBT. The possible mechanisms responsible for the effects of BCG on K562 cells and their possible clinical implications are discussed.

Depressed natural killer cell activity in schizophrenic patients.

Factors that suppress natural killer (NK) cell activity were examined in a random sample of 73 schizophrenic patients. NK activity in these patients were compared with 25 healthy age, sex and race matched controls. The mean percent of NK activity was 21% in the schizophrenic group compared with 30% percent in the controls. The difference between these two groups was statistically significant. The mean percent of NK activity in the chronic undifferentiated schizophrenic subgroup and schizoaffective subgroup were 20% and 22% respectively. The degree of suppression of NK activity in the chronic undifferentiated subgroup was higher than in the schizoaffective one, but the difference was not statistically significant. The two subgroups were comparable regarding other immune related variables such as total white cell count, neutrophils, lymphocytes, total protein, albumin, globulin, immunoglobulins and stress. The lower impairment of NK activity in the schizoaffective subgroup may be due to their exposure to lithium which can enhance immune functions. Factors associated with significant suppression of NK activity in schizophrenic patients were physical restraint, number of psychotropic medications, number of chronic non-psychiatric diagnoses and race. Psychosocial stressors were associated with suppression of NK activity but it was not statistically significant. Our results identify factors associated with reduced NK activity observed in certain schizophrenic patients and NK activity in these patients may be the result of interaction between various factors.

Central interferon-alpha inhibits natural killer cytotoxicity through sympathetic innervation.

The brain has been known to produce high levels of interferon-alpha (IFN-alpha) during viral infections. We investigated the central and peripheral mechanisms of the brain IFN-alpha-induced suppression of natural killer (NK) cytotoxicity in the rat. The activity of NK cells in the spleen and the peripheral blood decreased 30-120 min after intracerebroventricular (icv) injection of recombinant human IFN-alpha of > 1,000 U but not after its intraperitoneal injection. This effect was antagonized by pretreatment with icv naltrexone (NLTX). Splenic denervation was observed to completely abolish the IFN-alpha-induced suppression of NK activity, whereas bilateral adrenalectomy did not. Furthermore, this immunosuppression was blocked by an icv injection of an antagonist of corticotropin-releasing factor (CRF), alpha-helical CRF-(9-41). The icv injection of CRF resulted in reduced NK activity, which was not affected by NLTX. The results suggest that brain IFN-alpha activates the CRF system through central opioid receptors and thereby suppresses the NK cytotoxicity predominantly through splenic sympathetic innervation.

Immunosuppression by human gangliosides: II. Carbohydrate structure and inhibition of human NK activity

Gangliosides shed by tumors enhance tumor formation, possibly by suppressing host antitumor immune function, and gangliosides purified from animal tissues and cultured cells inhibit human cellular immune function in vitro. Determination of immunosuppressive activity of highly purified gangliosides, to uncover structure-activity relationships, is therefore important. Here we have studied a series of gangliosides obtained from human tissue and determined their effects on human natural killer (NK) activity. Total gangliosides from human brain tissue were moderately inhibitory; 100 nmol/ml reduced NK activity of human nonadherent PBMC by 43%. The influence of carbohydrate structure upon inhibitory activity was determined by study of eight highly (HPLC) purified individual gangliosides. Of these, we unexpectedly found that the two minor brain gangliosides with the simplest carbohydrate structures, G M2 and G M3 , were very active inhibitors (75 and 47%, respectively, at 50 nmol/ml). In contrast, the structurally more complex major species, G M1 , G D1a , G D1b , G T1b , and two other minor gangliosides, G D2 and G D3, were inactive. Reduced effector-target binding in a single-cell binding assay by G M2 but not G M3 suggests different mechanisms of inhibition by these two active gangliosides. Since G M2 and G M3 are present in high concentrations in, and are shed by, several common human tumors (e.g., neuroblastoma, melanoma, and glioma), their ability to inhibit NK cytotoxicity supports the hypothesis of a role of shed tumor gangliosides in the enhancement of tumor formation.