Normal Natural Killer Activity Research Articles

Natural killer (NK) cell activity during HIV infection: a decrease in NK activity is observed at the clonal level and is not restored after in vitro long-term culture of NK cells.

NK cell activity is impaired in HIV-infected patients. The mechanisms behind the altered NK functions are not clear, and conflicting data concerning NK and antibody-dependent cellular cytotoxicity (ADCC) activity have been reported. In order to investigate whether this impairment is also observed at the clonal level and whether it is related to a defect at the target cell binding and/or the post-binding level, we evaluated highly purified NK cell lines and cloned NK cells obtained from 22 HIV-infected patients at different stages of disease and compared them with normal controls for their ability to: (i) kill K-562 and U-937 cell lines using a 51Cr release assay; (ii) bind and kill K-562 and U-937 cells at the single cell binding level; (iii) release NK cytotoxic factor (NKCF), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma); (iv) kill anti-IgM preincubated Daudi cell line (ADCC activity). This study with cloned NK cells or NK cell lines from HIV-infected individuals showed: (i) a decrease in their lytic capability against target cell lines; (ii) a low ability to form conjugates with K-562 and U-937 cell lines with respect to controls; (iii) a decreased ability to kill bound target cells; (iv) low levels of released NKCF, TNF-alpha and IFN-gamma after incubation with U-937 cells. Taken together, these findings suggest that the impaired NK cell function during HIV infection is also observed at the clonal level and is related to defects both at the target and post-binding levels. However, the precise mechanisms remain to be determined. The inability to restore normal NK activity after long-term culture in the presence of high levels of recombinant IL-2 is in agreement with the hypothesis of a 'general anergic process' during HIV infection.

In Vitro Modulation of Cellular Immunity with Antioxidants in Patients with Thalassemia Major.

Immunological disturbances have been reported in thalassemia and the possibility has been raised that these may be consequences of blood transfusion and iron overload. These disturbances are augmentation of the number of supressor T cells (CD8), decreased number and activity of helper T cells (CD4) and impaired activity of NK (natural killer) cells. Iron overload causes toxic tissue changes through the release of free radicals and induces oxidative stress. According to Fenton and Haber-Weiss reactions, iron plays a catalytic role occuring hydroxyl radicals (OH*) which are very reactive free radicals. Antioxidants, like vitamin E, vitamin C and selenium, may modulate oxidative damage.In the present study; firstly, normal lymphocytes mitogen responses and NK activity were investigated by colorimetric MTT test in 26 thalassemia patients and 10 healthy volunteers as control. Secondly, lymphocytes were incubated with vitamin E ( 150, 50, 15 mg/ml), vitamin C (200, 100, 20mg/ml) and selenium (10−5, 10−6, 10−7 M). Finally, lymphocytes mitogen responses and NK activity are investigated. The results were statistically analyzed comparing with controls and healthy volunteers.It was found decreased NK activity of thalassemia patients in comparison with healthy volunteers. The concentration of 10−7 M of selenium enhanced NK activity at the E:T (effector/target) ratio of 50:1 The concentration of 200 mg/ml of vitamin C enhanced NK activity at the E:T ratio of 10:1, 25:1 and 50:1. However, vitamin E decreased NK activity of both thalassemia patients and healhty volunteers. The concentration of 50 mg/ml vitamin E decreased NK activity at the E:T ratio of 5:1 in thalassemia patients and the concentration of 15 mg/ml of vitamin E decreased NK activity at the E:T ratio of 5:1 in healhty volunteers.It was not found any differences between thalassemia patients and healthy volunteers in lymphocytes mitogen responses. The concentration of 200 mg/ml of vitamin C decreased lymphocytes mitogen response against PHA.In conclusion, we suggest that vitamin C and selenium supplementation are required in patients with thalassemia for augmentation of NK cell activity.

Impairment of natural killer cell activity in Chlamydia trachomatis infected individuals.

Natural killer (NK) cell activity is impaired in Chlamydia trachomatis-infected patients. The mechanisms behind the altered NK functions are not clear, but data concerning NK and antibody-dependent cellular cytotoxicity (ADCC) activity have been reported. To investigate whether this impairment is related to a defect at the target cell binding and/or the postbinding level, we evaluated highly purified NK cells obtained from 125 C. trachomatis-infected patients and compared them with 101 normal controls for their ability to kill K-562 and U-937 cell lines using a 51Cr release assay; release tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma); and kill anti-IgM preincubated P-815 cell line (ADCC activity). We found a decrease in the lytic capability of NK cells from C. trachomatis-infected patients against target cell lines; decreased ability to kill bound target cells; and low levels of released TNF-alpha and INF-gamma after incubation with U-937 cells. Taken together, these findings suggest that the impaired NK cell reaction during chlamydial infection is related to defects both at the target and postbinding levels. However, the precise mechanisms remain to be determined. The inability to restore normal NK activity after long-term culture in the presence of high levels of recombinant IL-2 support the hypothesis of an anergic process during chlamydial infection.

Natural killer cell activity in patients with Graves' disease and Hashimoto's thyroiditis.

Natural killer (NK) cell activity of peripheral blood lymphocytes (PBL) against k562 human tumor cell targets was studied in patients with Graves' disease and Hashimoto's thyroiditis. NK activity was measured in a standard 4-hour 51chromium (Cr) release assay. Cytotoxicity was expressed as lytic units (LU)/10(6) PBL. Significantly decreased NK cell activity was demonstrated in both groups of patients, with mean (+/- SE) lytic units of 10.3 (+/- 9.1) and 13.3 (+/- 10.3) for patients with Graves' disease and Hashimoto's thyroiditis, respectively, compared with 36.0 (+/- 26.3) for age- and sex-matched normal subjects. When patients with Graves' disease were analyzed according to their thyroid status; NK activity was significantly depressed in (1) hyperthyroid patients before treatment; (2) hyperthyroid patients receiving antithyroid therapy; and (3) euthyroid patients receiving antithyroid therapy, compared with normal subjects. Graves' disease patients who were hypothyroid after radioactive iodine therapy or thyroidectomy had normal NK activity. No significant differences between hyperthyroid and euthyroid patients or between hypothyroid patients and normal subjects were demonstrated. NK activity in patients with Graves' disease did not correlate with serum levels of thyroxine, the presence or severity of ophthalmopathy, or titers of serum thyroid antibodies. In patients with Hashimoto's thyroiditis there was no correlation between NK activity and goiter size, titers of antithyroid antibodies, or thyroid status. These findings suggest that depression of NK activity in both disorders is secondary to abnormalities of thyroid hormone secretion, although an effect of the underlying autoimmune reactions has not been excluded.

Importance of natural killer cells in the rejection of hamster skin xenografts.

In the hamster to rat xenogeneic combination, antibodies, T cells, and natural killer (NK) cells have all been implicated in the process of rejection. 3.2.3 is a mouse IgG1kappa monoclonal antibody (mAb) directed against NKR-P1A on rat NK cells. The purpose of this study was to evaluate the effect of this mAb independently and in combination with other immunosuppressive agents in a hamster to rat skin graft model in order to elucidate the mechanisms involved in xenograft rejection. Lewis rats were recipients of hamster skin grafts. Various groups received antilymphocyte serum (ALS) (days -1, 0, and +2), rapamycin (3 mg/kg; alternate days from day +1 through day +13), and 3.2.3 mAb (days 0, +1, and +2). Anti-hamster antibody production was determined serially with a complement-dependent cytotoxicity assay. Lewis anti-hamster mixed lymphocyte reaction and cell-mediated lympholysis assays were performed within 7 days after rejection of the skin graft. NK cell function was tested using a cytotoxicity assay versus YAC-1 target cells on day 14 or day 15 after skin grafting. Median graft survival in untreated animals was 7 days. There was only modest prolongation in rats treated with rapamycin alone (median survival time [MST]=9 days) or ALS alone (MST=10 days). The use of 3.2.3 mAb in untreated rats (3.2.3 alone MST=7 days) and in ALS-treated rats (ALS+3.2.3 MST=9.5 days) did not improve graft survival. The combination of ALS+rapamycin substantially improved graft survival (MST=13 days), and even greater prolongation was seen with the addition of 3.2.3 mAb (ALS+rapamycin+3.2.3 MST=18.5 days). Cytotoxic antibodies, secondary mixed lymphocyte reaction responses, cytotoxic T cells, and normal NK activity were seen at the time of rejection in untreated rats as well as those treated with 3.2.3 mAb alone, ALS alone, ALS+3.2.3 mAb, and rapamycin alone. ALS+rapamycin completely blocked the formation of anti-hamster antibodies and cytotoxic T cells but did not suppress NK activity. The use of 3.2.3 mAb produced a marked but transient suppression of NK activity in all groups. Hamster skin xenografts can be rejected by Lewis rats in the absence of cytotoxic antibodies and cytotoxic T cells. ALS, rapamycin, and ALS+rapamycin do not suppress NK activity in Lewis rats, although their use produces a modest prolongation of hamster skin graft survival. The administration of 3.2.3 mAb to Lewis rats results in a marked but transient suppression of NK cell function, which substantially prolongs hamster skin graft survival only when antibody and cytotoxic T-cell production have also been suppressed.

Relationship of curative surgery on natural killer cell activity in colorectal cancer.

Aim of this study has been to evaluate natural killer (NK) activity in patients with colorectal tumors before and after curative surgery. Forty colorectal cancer patients without distant metastases were stratified according to American Joint Committee on Cancer/International Union Against Cancer staging system into three categories: Stage I (n = 12), Stage II (n = 15), and Stage III (n = 13). All of them underwent curative resection, and there were no major postoperative complications. Venous blood samples were obtained preoperatively, at surgical wound closure, and on the 1st, 7th, and 21st postoperative days. Mononuclear cells were isolated over Ficoll-Hypaque (Lymphoprep, Nycomed Pharma AS, Oslo, Norway) gradients, and NK activity was assayed by evaluation of cytotoxic response against K562 cells. Normal NK activity was achieved from 15 healthy donors. Percentage relative increments in relation to preoperative levels were calculated for every postoperative sample, and t-test was used for statistical evaluation. Before surgery, Stages II and III patients had lower levels of NK activity than healthy people (P < 0.05 and P < 0.001, respectively). NK activity always fell after surgery (Stage I: -18.48 +/- 11.42; Stage II: -16.93 +/- 13.57; Stage III: -35.29 +/- 12.03, at day 1 postsurgery) and appeared to rise slightly by the 21st postoperative day in Stage I patients (+4.87 +/- 12.41). Stage II, and especially Stage III, patients did show a significant recovery by the 21st postoperative day (+23.63 +/- 9.36 and +43.19 +/- 13.34, respectively). At this time, NK activity in these two groups was not significantly lower than in normal subjects (P > 0.05). NK activity is depressed in colorectal cancer patients in relation to progression of illness, even at locoregional stages. Curative resection of tumors at Stages II and III has promoted a recovery of NK activity in patients with uneventful postoperative courses.

Allo-skin graft rejection, tumor rejection and natural killer activity in mice lacking p56lck.

Mice lacking the p56lck molecule (lck -/-) have a profound block in the maturation of thymocytes and a greatly reduced number of peripheral mature T cells. To analyze further the functions of the T cells developed in lck -/- mice in vivo, we evaluated the ability of lck -/- mice to reject allo-skin grafts and methylcholanthrene (MCA)-induced syngeneic fibrosarcoma, and also examined the biological activity of lck -/- natural killer (NK) cells. Mice lacking p56lck failed to reject skin grafts from either MHC-disparate or minor-histocompatibility-different donors, even after they had been primed with donor spleen cells. They also failed to reject the MCA-induced immunogenic syngeneic fibrosarcoma, MC57X. NK activity in mice lacking p56lck was normal, and there were no differences in the NK cell activation induced by poly(I).poly(C) stimulation or interleukin-2 stimulation (lymphokine-activated killer induction) between mice lacking p56lck and their immunocompetent heterozygous littermates. NK cells lacking p56lck mediated a normal antibody-dependent cell-mediated cytotoxicity (ADCC) response. The results of this study indicate that the loss of p56lck severely impairs the effectors of the immune system which mediate the rejection of allo-skin grafts and syngeneic tumors. The normal NK activity in lck -/- mice suggests that p56lck is not required for the development and activation of NK cells.

Initiated stem cells in murine intestinal carcinogenesis: prolonged survival, control by NK cells, and progression.

Weekly injections of dimethylhydrazine (DMH) (25 mg/kg), or azoxymethane (AOM) (8 mg/kg) to young adult male CDI mice for 1-2 months produced generalized intestinal crypt hyperplasia, which we measured in duodenum in terms of number of interphase and mitotic cells present in crypts. As shown earlier, the crypts expanded because of the presence of a hyperproliferative "initiated" crypt subpopulation which was also sensitive to natural killer (NK) cells. Hyperplasia was thus present as long as NK activity was suppressed by the carcinogen treatment. After interruption of the treatment for periods of 1, 2, 3, 6 and 10 months in the various groups, hyperplasia soon regressed as a result of elimination of the subpopulation by the recovering NK cells. When NK activity was once again eliminated during the terminal days of these "interruption periods" (by injections of anti-asialo GM-I antibody, alpha AGM-I), the original hyperplasia was fully reconstituted, apparently from stem cells of the subpopulation which survived up to 10 months in their crypt base location. These "initiated stem cells" represented, then, the original carcinogenic insult during the pre-cancerous period. They also appeared to be the source of the eventual neoplasia, as treating the animals with mutagens during the interruption periods produced specific changes in crypt base histology: new "crypt base basophilic" (CBB) cells appeared which produced large accumulations as well as microscopic tumors when NK activity was suppressed (by alpha AGM-I). Some of the initiated stem cells were apparently transformed into neoplastic ones which remained under NK control, the NK cells preventing the establishment of their progeny. Further experiments indicated that, although the initiated stem cells are not eliminated by normal NK activity, activated NK cells can kill them, thereby eliminating the potential source of neoplasia.

Interferon beta enhances the natural killer activity of patients with bladder carcinoma.

We have investigated the effect of interferon beta (INF beta) on the natural killer (NK) cytotoxic activity of peripheral blood mononuclear cells (PBMC) from patients with superficial and infiltrative transitional-cell carcinoma of the bladder (TCC) against both NK-sensitive and NK-resistant target cells. The normal NK activity found in PBMC from these patients can be significantly enhanced by short-term incubation (18 h) with INF beta (P < 0.05). The depressed NK cytotoxic activity found in PBMC from patients with infiltrative TCC can also be significantly enhanced, but not normalized, by short-term incubation with INF beta (P < 0.05). In kinetic studies we found that the maximal levels of the INF beta-promoted cytotoxic activity against NK-sensitive and against NK-resistant target cells in PBMC from TCC patients were reached after 18 h of culture. Short-term-INF beta-incubated PBMC from patients with TCC of the bladder also showed marked cytotoxic activity against NK-resistant target cells. The effector cells of the INF beta-induced cytotoxic activity in PBMC from patients with TCC were CD16+ CD3- NK cells. This cytotoxic inducer effect of INF beta synergized with that of interleukin-2. In conclusion, INF beta can enhance the NK activity of PMBC from patients with TCC of the bladder.

A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene.

A severe immunodeficiency involving a complete loss of T lymphocytes and natural killer cells was observed in independent lines of transgenic mice containing > 30 copies of the human CD3E gene (pL12). T-cell- natural killer (NK)- mice could also be generated by using a gene fragment pL12 delta 1 (without exons 4A and 5) coding for the CD3-epsilon transmembrane region and its 55-amino acid nonenzymatic cytoplasmic tail. The abnormally small thymus gland in the homozygous transgenic animals, which was approximately 1% the size of a wild-type thymus, contained only a few (2-4%) prethymocytes with a Thy-1+Pgp-1+IL-2R alpha- CD3-4-8- phenotype. In mice with lower copy numbers of the transgene thymocyte development was blocked at the Thy-1+Pgp-1-IL-2R alpha+CD3-4-8- stage, and normal NK activity was detected. Mice generated with high-copy numbers of a transgene pL12 delta 2 (pL12 delta 1 minus exons 6), coding for a truncated protein from which the CD3-epsilon extracellular domain, its transmembrane region, and most of its cytoplasmic region were absent, contained normal numbers of T lymphocytes and NK cells. These transgene effects suggested that recruitment of signal-transduction molecules by the cytoplasmic tail of this protein played an important role in the abrogation of both lineages. Taken together these observations support the notion that T lymphocytes and NK cells stemmed from a common precursor.

Rapid restoration of natural killer activity following treatment with 2‐chlorodeoxyadenosine in 22 patients with hairy‐cell leukemia

We report on the T-cell profile and natural killer (NK) function in 22 hairy cell leukemia patients before and 2 and 6 months after a single 7-day course of 2-CdA therapy at a dose of 0.1 mg/kg daily continuous infusion. Before treatment, two groups of patients were identified in respect to NK activity: the first (12/22) had a normal number of T and NK cells and a normal NK activity, the second (10/22) showed a severe reduction of CD3+, CD4+, CD16+, and CD56+ cells, together with impaired NK activity. All patients had increased serum levels of the soluble interleukin 2 receptor (sIL-2R). Along with a high complete remission rate (77%), treatment with 2-CdA produced a significant reduction (p = 0.001) of total lymphocytes (from 1.59 x 10(9)/l to 0.72 x 10(9)/l), and particularly of CD4+ cells (from 0.68 x 10(9)/l to 0.23 x 10(9)/l), while CD8+, CD16+ and CD56+ cells were less affected. Despite the dramatic reduction of lymphocytes which lasted for more than 6 months, 7/10 patients with impaired NK function before starting 2-CdA therapy normalized the cytotoxic function within 2 months. In conclusion, 2-CdA produces a severe reduction of lymphocytes in general, and of CD4 lymphocytes in particular, whilst it may produce a significant increase in the proportion of NK cells leading, together with a normalization of the sIL-2R serum levels, to a rapid restoration of the NK cytotoxic function in the majority of patients.

Suppression of natural killer cell activity by granulocytes in patients with aplastic anemia: role of granulocyte colony-stimulating factor

Patients with aplastic anemia were tested for natural killer (NK) activity, and the roles of granulocytes and granulocyte colony-stimulating factor (G-CSF) in the regulation of cytotoxicity were evaluated. Blood lymphocytes showed low or no NK activity against K562 targets. The depression of NK activity was more frequently recorded for patients who were not in remission and those who received G-CSF administration. Granulocytes of aplastic anemia patients with impaired NK activity suppressed the lytic activity of NK cells. By contrast, granulocytes from normal controls and aplastic anemia patients with normal NK activity had no suppressive activity. There was a good correlation between NK activity of lymphocytes and suppressive activity of granulocytes. Blocking of direct contact of suppressor and effector cells by cell chambers abolished suppression of cytotoxicity. NK suppression by granulocytes was resistant to treatment with catalase or superoxide dismutase. In vitro stimulation with G-CSF of granulocytes that naturally had no suppressive activity resulted in development of suppressive function, whereas granulocytes with natural suppressive activity were not further stimulated in vitro by G-CSF to express augmented activity. These results suggest that the presence of suppressor granulocytes in the blood could be one cause of the impaired NK activity in patients with aplastic anemia.

Inhibition of normal natural killer cytotoxicity by sera from hemophilic patients

In this study we searched for circulating antibodies or other serum factors that could account for the natural killer (NK) defect observed in hemophiliacs (He) infected with the human immunodeficiency virus (HIV). We analyzed the effect of negative or positive sera for HIV from He on normal NK activity. We showed that sera from He interfered with normal NK cytotoxicity. The inhibitory activity was higher in HIV + sera and increased as the HIV disease progressed. HIV − sera also inhibited NK function, although to a lesser extent than HIV +, and it was probably due to isoimmunization through replacement treatment with plasma-derived concentrates. For each individual, no direct correlation was found between NK inhibition (NK-INH) of sera and the NK activity of He peripheral blood mononuclear cells (PBMC). Furthermore, He serum was poorly inhibitory on autologous PBMC. Preincubation of allogenic effector or target cells with He sera revealed that the inhibitory effect was the result of the reaction with these cells. A positive correlation was found by comparing NK-INH of whole He sera with the serum levels of circulating immune complexes. When the NK-INH assay was performed using the same concentration of DEAE-purified IgG from N, HIV − or HIV +, we found that HIV + AIDS IgG was more inhibitory than the others.

Cyclophosphamide-induced suppressor cells in nude mice.

Lymphocytes regenerated after treatment with a high dose of cyclophosphamide (CY) were characterized in nude mice. Ten days after a single injection of 200 mg/kg CY into nude mice, regenerated spleen cells suppressed in vitro primary and second antibody production against sheep red blood cells. The CY-treated spleen cells exhibited normal natural killer (NK) activity, very low B and T cell content, but increases in cell surface charge [electrophoretic mobility (EPM)] and histamine receptors. The suppressor cells could not be removed by treatment with anti-Thy-1 plus complement (C), or treatment with antiasialo GM1 (aGM1) plus C, which abrogated NK activity. It was concluded that CY-treated spleen cells, which exhibited high EPM and histamine receptors, comprise the natural suppressor cells which are Ig-, Thy-1- and aGM-1.

Functional impairment of natural killer cells in active ulcerative colitis: reversion of the defective natural killer activity by interleukin 2.

We have studied the functional characteristics and clinical importance of the natural killer (NK) cytotoxicity of peripheral blood mononuclear cells (PBMNC) from patients with ulcerative colitis. Normal NK activity was observed in PBMNC from patients with inactive disease, but a pronounced decrease was found in those with active disease. Clinical change from active to inactive disease was associated with enhancement of the depressed NK activity. The impairment of NK cytotoxicity found in patients with active disese could not be ascribed to a deficient number of NK cells as the amounts of HNK-1+, CD16+ (Leu 11), and CD11b (OKM1) cells in PBMNC were within normal ranges. This defective cytotoxic PBMNC activity was normalised by short term (18 hour) incubation with recombinant interleukin 2 (rIL-2). Moreover, long term (5 day) incubation of these effector cells with rIL-2 induced strong cytotoxic activity against NK resistant and NK sensitive target cells in patients with active and inactive disease. We also found that both precursors and effectors of cytotoxic activity promoted by short term and long term incubation with rIL-2 of PBMNC from the patients showed the phenotype of NK cells (CD16+, CD3-). Taken together, these results show that active ulcerative colitis is associated with a defective function of NK cells that is found to be normal in the inactive stage of the disease. The possible pathogenic and therapeutic implications of these findings are discussed.

NK cell activity in treated prostate cancer patients as a probe for circulating tumor cells: hormone regulatory effects in vivo.

Natural killer (NK) cell activity was studied together with tumor marker serotests (PSA, PAP) and blood testosterone, estradiol, cortisol, and prolactin concentrations in treated prostate cancer patients. NK cell activity data were correlated with tumor stage (stage D0 + D1 versus stage D2) and showed statistically insignificant differences. Both tumor progression and stabilization of metastatic disease, triggered by the application of more appropriate therapy in progressive subjects, yielded low NK activity data. By contrast, normal NK activity was found during both partial remission of stage D2 tumor and stabilization of the same disease, after an initial period of tumor remission. Differences between NK activity data from the aforementioned two groups are statistically significant (P less than 0.01). In subjects examined, the application of NK activity assay to those with advanced disease reflected changes in the outcome of the treatment more closely than it did routine tumor marker assessment. The activity of NK cells seems unaffected by changes in basal blood estradiol, cortisol, testosterone, and prolactin concentrations that occur during therapy with pharmacological agents (estradiol, cyproterone acetate, diethylstilbestrol, and flutamide) and during surgical castration. The reported NK activity recordings in treated prostate cancer patients might be indicative of the presence of tumor cells in the circulation. If this holds true, the measurement of NK activity would appear to furnish urological oncology with a new tool for early, rapid recognition of progressive metastatic tumors.

Thymosin alpha one restores murine T-cell-mediated responses inhibited by In vivo cocaine administration

The effects of different in vivo thymosin alpha one (Tα1) treatments on T-cell responses inhibited by cocaine abuse were studied. Administration during cocaine treatment promoted a faster recovery of normal natural killer (NK) cell activity after the suspension of abuse. Suspension of cocaine plus repeated Tα1 administrations strongly restored NK activity and, interestingly, spleen cells from mice treated with Tα1 during and after cocaine administration achieved a very rapid recovery and the greatest stimulation of natural cytotoxicity. This last treatment also restored the cocaine-inhibited specific T-cell response (i.e. allogeneic cytotoxic T-lymphocyte (CTL) generation) and abrograted the cocaine-induced suppression of interferon gamma (IFN-γ), interleukin 2 (IL-2) and IL-4 production. Finally restoration and induction of thymic cellularity were significant when Tα1 was given during and after cocaine administration. The present investigation provides evidence for the first time that thymic hormones could be of potential value in controlling cocaine-induced impairment of T-cell-mediated immunity in the mouse.

Two different maturational stages of natural killer lymphocytes in human newborn infants

The objective of this study was to assess the basis for the diminished natural killer (NK) lymphocyte activity of neonates. We found either severely reduced (63% of 68 neonates) or normal (similar to healthy adult) levels of NK activity. The percentages of cord blood mononuclear cells from the two groups of infants that expressed CD16, a differentiation antigen found in NK cells, were similar and within the range found in peripheral blood mononuclear cells of adults. However, infants with low NK activity had reduced numbers of cells in the CD16+56+ subpopulation, whereas the number of these effector cells present in cord blood mononuclear cells from infants with normal NK activity was within the range found in adults. Recombinant interleukin-2, but not recombinant interferon-gamma, normalized the low NK activity of infants in a dose- and time-dependent manner. Analysis of the pattern of target cell susceptibility to lysis, together with the CD16+CD3- phenotype of the precursor and effector lymphocytes, demonstrated that the induced cytotoxicity was mediated by NK cells. In contrast, NK cells from infants with normal cytotoxic levels exhibited a functional response to interleukin-2 and interferon-gamma similar to that of adults. Our results indicate that NK cells in human neonates go through two different maturational stages.

Natural killer and lymphokine activated killer cell functions in Hodgkin's disease

We report the natural killer (NK) and lymphokine activated killer (LAK) cell activities in peripheral blood lymphocytes (PBL) from untreated patients with Hodgkin's disease (HD) and from healthy donors. The frequency of LAK cell precursors was also studied using limiting dilution analysis (LDA). About 75% of the HD patients had normal NK activity. There was a higher percentage of low NK responders (mean percent NK activity of healthy donors--2 SD) in patients with lymphocyte depletion histologic grade of the disease and those who were in clinical stage IV, suggesting a correlation of decrease in NK activity with poor prognosis. We found efficient LAK activity against the NK-sensitive K562 cells and NK-resistant VIP (melanoma) and T-24 (bladder carcinoma) tumour targets in both low and normal NK responder HD patients, irrespective of the histopathological grade and clinical stage of the disease. In concordance with their good LAK cell activity, HD patients showed a frequency distribution of LAK cell progenitors in the PBL comparable to that of healthy donors.

Decreased natural killer (NK) activity in patients with myeloproliferative disorders.

Natural killer (NK) cell number and activity were measured in 26 patients with myeloproliferative disorders and the results were compared with 16 age-matched control patients. The percent of Leu-11b-positive cells was 11% +/- 3% in the patients, compared with 12% +/- 4% in the control patients. Ten of 26 patients, however, had NK activity lower than all of the control values at three different effector to target cell ratios (E:T) (P less than 0.005). The values of those patients with low unstimulated NK activity remained low despite stimulation with interleukin-2 (IL-2) or alpha-interferon (alpha-IFN), whereas the values of those patients with normal unstimulated activity responded to IL-2 and alpha-IFN like the control patients. Three of the ten patients with low NK activity had a history of malignant neoplasms. None of the 16 patients with normal NK activity had a history of malignant neoplasms (P less than 0.05). We conclude that patients with myeloproliferative disorders frequently have low endogenous NK cell activity in vitro. The dysfunction of the NK system appears to be intrinsic because the relative number of NK cells was similar to control values and the response to stimulation with IL-2 and alpha-IFN was suboptimal. There may be a relationship between low NK activity and the development of malignant disease in such patients.