Human recombinant IL-4 decreases the emergence of non-specific cytolytic cells and favours the appearance of memory cells (CD4+CD45RO+) in the IL-2-driven development of cytotoxic T lymphocytes against autologous ovarian tumour cells.

As IL-4 and IL-6 have also been reported to promote the development of T lymphocytes such as IL-2, we investigated their role in the development of specific cytotoxic T lymphocytes (CTL) against autologous ovarian tumours in mixed lymphocyte tumour cultures (MLTC). Peripheral blood lymphocytes (PBL) from five ovarian carcinoma (OC) patients were incubated with autologous OC cells at a PBL:OC cell ratio of 20:1 in IL-2 alone (50 U/ml for the first week and 200 U/ml thereafter) or with IL-4 (100 U/ml) and/or IL-6 (5 U/ml). Neither IL-4 nor IL-6 improved lymphocyte proliferation consistently. In contrast, IL-4 reduced significantly the development of LAK activity as assayed against Daudi cell line, and decreased modestly the emergence of natural killer (NK) activity as assayed against K562. This property was not shared by IL-6. The prevention of the development of non-specific cytolytic activity (LAK and NK activities) was much stronger when the MLTC was started with IL-4 in the absence of IL-2 during the first week in culture. A concomitant drop in NKH-1 expression (CD56) was observed. By inhibiting the emergence of non-specific cytotoxicity, IL-4 provided better evidence of the specific cytolytic activity directed at ovarian cells. In parallel, a significant increase in the generation of memory cells (CD4+CD45RO+) was observed with IL-4. In conclusion, in this model, IL-4 added before IL-2 decreases significantly the emergence of non-specific cytotoxic cells, and promotes the generation of memory cells. These properties may be of interest in the design of strategies aimed at obtaining tumour-specific cells for investigational and immunotherapeutic purposes.     

VIP restores natural killer cell activity depressed by hepatitis B surface antigen.

Vasoactive intestinal peptide (VIP) has recently been shown to bind to human lymphocytes and modulate immune functions. The ability of VIP in restoring natural killer (NK) cell activity depressed by hepatitis B surface antigen (HBsAg) has been investigated in the present research. Human lymphocytes were incubated with HBsAg and, after washing, a 4-hr cytotoxicity assay was performed. VIP was coincubated with lymphocytes during the preincubation with HBsAg or, alternatively, throughout the cytotoxicity assay. The study revealed that VIP, either preincubated or coincubated in the 4-hr assay, strongly restores NK cell activity depressed by viral antigen. This is noteworthy considering that a number of lymphocyte modulators such as interferons fail in restoring viral-dependent NK cell activity depression. In contrast with previous reports, even when coincubated in the 4-hr assay, VIP is a strong activator of NK cell activity. Further studies will be required to understand which mechanisms are involved in the interrelation between VIP and NK cells during viral infections.     

Evidence that induction and regulation of lymphokine-activated killer (LAK) activity are mediated by changes in tumour-binding potential of lymphocytes after activation by interleukin-2 (IL-2).

The changes in the tumour-binding potential of human peripheral blood lymphocytes (PBL) after activation by interleukin-2 (IL-2) was investigated by directly counting the number of lymphocytes bound to lined hepatoma cell monolayers. A significant increase in the tumour-binding potential of PBL was found after activation by more than 100 U/ml of IL-2. Maximal tumour-binding potential was achieved at 1000 U/ml of activation, and an overdose of IL-2 activation slightly decreased this potential. These changes were almost exactly the same as the changes in anti-tumour cytotoxicity as measured by a 4-hr 51Cr-release assay. In addition, the kinetics of tumour binding by lymphokine-activated killer (LAK) cells was shown to be almost identical to that of tumour cell lysis. These results thus provide evidence that induction and regulation of LAK activity are mediated by changes in tumour-binding potential of lymphocytes after activation by IL-2.     

Enhancement of Antibody-Dependent Cellular Cytotoxicity of Neonatal Cells by Interleukin-2 (IL-2) and IL-12

Newborn infants are more susceptible to infections due in part to deficiencies in the cytotoxic functions of their lymphocytes. We investigated the ability of interleukin-2 (IL-2) and IL-12 to enhance the cytotoxicity of neonatal (cord blood) and adult mononuclear cells (MNCs) in both natural killer (NK) cell and antibody-dependent cellular cytotoxicity (ADCC) assays. The cytotoxic activity of cord blood MNCs was less than 50% that of adult MNCs in most assays prior to exposure to cytokines. Incubation with IL-2 (100 U/ml) or IL-12 (1 ng/ml) for 18 h increased the NK cell activity (using K562 target cells) of both cord blood and adult MNCs, and the combination of IL-2 and IL-12 increased cord blood cytotoxicity threefold, making the cytotoxicity of cord blood cells equivalent to that of adult cells treated with the same cytokines. In ADCC assays with chicken erythrocyte targets, the combination of IL-2 and IL-12 increased the cytotoxicities of both cord blood and adult MNCs, with greater enhancement again seen with cord blood cells. In assays with NK cell-resistant CEM cells coated with human immunodeficiency virus (HIV) gp120 antigen in the presence of hyperimmune anti-HIV immunoglobulin, ADCC of cord blood MNCs was about 50% that of adult MNCs; ADCC of cord blood MNCs increased two- to threefold with the addition of IL-2 and IL-12, whereas ADCC of adult MNCs did not increase. Incubation of cord blood cells, but not adult cells, with IL-2 or IL-12 for 1 week increased the percentage of CD16⁺/CD56⁺ cells two- to fivefold and enhanced ADCC activity. Thus, IL-2 and IL-12 greatly enhance both the NK cell and ADCC activities of neonatal MNCs and increase the number of NK cells in longer-term culture.     

Preclinical Studies Using Immobilized OKT3 to Activate Human T Cells for Adoptive Immunotherapy: Optimal Conditions for the Proliferation and Induction of Non-MHC-Restricted Cytotoxicity

In order to obtain large numbers of T cells for adoptive immunotherapy after bone marrow transplantation (BMT), we optimized conditions for long-term proliferation of T cells that exhibit non-MHC-restricted cytotoxicity using immobilized anti-CD3 (OKT3) activation and culture in IL-2. Proliferation and cytotoxicity directed at Daudi, K562, and B cell lines were used to determine (1) the optimal concentration of IL-2 and the optimal time of exposure to immobilized OKT3 for maintaining growth and cytotoxicity, (2) the starting populations that can be used, (3) the T cell subsets that mediate cytotoxicity, and (4) the optimal medium and concentration of serum for maintaining growth and cytotoxicity. Peripheral blood lymphocytes (PBL) activated with OKT3 would proliferate and mediate cytotoxicity at IL-2 doses as low as 30 IU/ml. Increasing the IL-2 concentrations beyond 600 IU/ml did not augment the proliferative or cytotoxic responses of PBL. A 24-hr incubation on OKT3 was sufficient to activate PBL. Increasing the incubation time on OKT3 from 24 to 72 hr did not significantly enhance cytotoxicity. Comparisons between PBL and purified T cells (E-rosette) indicated that either cell population could be activated with OKT3 in the presence of IL-2 to proliferate and mediate non-MHC-restricted cytotoxicity. Purified populations of CD4⁺ or CD8⁺ T cells demonstrated equivalent proliferation and cytotoxicity when activated using IL-2 and OKT3. With equal concentrations of human or fetal bovine serum, RPMI 1640 and X-Vivo 10 were comparable for supporting proliferation and cytotoxicity. These conditions are being used to activate and expand T cells for clinical trials that involve infusing activated T cells into recipients after autologous BMT.     

Suppression of natural killer cell activity by surgical stress in cancer patients and the underlying mechanisms

The influence of surgical stress on the natural killer (NK) activity of peripheral blood lymphocytes in patients with carcinoma of the lung or gastrointestinal system was studied. The peripheral blood lymphocytes of the patients showed a marked decrease in NK activity against K-562 cells as target cells 1-2 days after surgery. The activity remained lowered for 2 weeks after thoractomy and for 1 week after laparotomy. No appreciable suppression of NK activity was observed with normal human peripheral blood lymphocytes preincubated with postoperative patient sera. Peripheral blood mononuclear cells obtained postoperatively from patients lost NK activity after ultraviolet irradiation, without any detectable loss of viability. Such irradiated mononuclear cells showed inhibition of NK activity after a 24-hour preincubation with peripheral blood lymphocytes from normal subjects. Similar suppressive activity was demonstrable in a fraction of mononuclear cells with adhesiveness to plastic petri dishes, while non-adherent cells had no such activity. When added immediately to the cytotoxicity assay system without the 24-hour preincubation, patient mononuclear cells caused no inhibition of NK activity, whereas adherent cells from normal subjects enhanced NK activity. The findings seems to indicate that, following surgical stress, plastic dish-adherent peripheral blood mononuclear cells become deprived of NK helper activity and exert suppression, thus causing postoperative depression of NK activity.     

Leukotriene B4 augments interleukin-2 receptor-beta (IL-2R beta) expression and IL-2R beta-mediated cytotoxic response in human peripheral blood lymphocytes.

Interleukin-2 can induce cytolytic activity in human peripheral blood lymphocytes and this activation is mediated by the beta chain of the interleukin-2 receptor-beta (IL-2R beta). Leukotriene B4 (LTB4) is a potent lipid inflammatory mediator which induces IL-2 and interferon-gamma (IFN-gamma) production from T cells. We examined the ability of LTB4 to modulate IL-2-induced cytolytic activity. Peripheral blood lymphocytes which had been preincubated for 24 hr in the presence of LTB4 responded to 100-fold lower concentrations of IL-2 with an augmentation of natural killer (NK) cell cytotoxic activity. Furthermore, incubation of lymphocytes with graded concentrations of LTB4 augmented the proportion of IL-2R beta+ cells. Peak activity was seen at 10 nM LTB4 and was comparable to that of PHA. By two-colour cytofluorometry, the increased expression of IL-2R beta was found predominantly on CD56+ cells and to a lesser extent on CD8+ cells, while CD4+ cells were unaffected. These observations were correlated at the messenger RNA (mRNA) level with increased IL-2R beta mRNA accumulation following stimulation of purified CD56+ and CD8+ cells with LTB4. CD56-, CD8- cells did not respond to LTB4 by increased IL-2R beta mRNA accumulation. Our data indicate, for the first time, that LTB4 can markedly increase the sensitivity of non-major histocompatibility complex (MHC)-restricted cytotoxic lymphocytes to IL-2, in terms of IL-2-dependent cytotoxic responses, and that this sensitivity is associated with augmented IL-2R beta gene message and cell surface expression.     

Inhibition of human NK cell function by valinomycin, a toxin from Streptomyces griseus in indoor air

Streptomyces griseus strains isolated from indoor dust have been shown to synthesize valinomycin. In this report, we show that human peripheral blood lymphocytes treated with small doses (30 ng ml(-1)) of pure valinomycin or high-pressure liquid chromatography-pure valinomycin from S. griseus quickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml(-1)) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml(-1) dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte-macrophage colony-stimulating factor and gamma interferon (IFN-gamma) production by NK cells. However, IFN-gamma production induced by a combination of IL-15 and IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect of the cytokine combination against valinomycin. Thus, valinomycin in very small doses may profoundly alter the immune response by reducing NK cell cytotoxicity and cytokine production.     

Comparative natural killer cell activities of thymic, bursal, splenic and intestinal intraepithelial lymphocytes of chickens

The natural killer (NK) cell activities of spleen, thymus, bursa, peripheral blood and gut intraepithelial lymphocytes (IEL) from FP and SC chickens were investigated in 4-hr and 16-hr 51Cr release assays. Target cells were 4 different tumor cell lines derived from either an avian leukosis tumor transplant (LSCC-RP9, LSCC-RP12) or from Marek's disease lymphomas (MDCC-MSB-1, MCDD-CU36). Great variability in cytotoxic potential was observed among NK cells of different lymphoid organs. NK cell cytotoxicity varied depending upon the type of effector cells, type of target cells, the ratio of effector to target cells, and the age and genetic background of chickens. Substantial levels of NK cell activity were detected in spleen and gut IEL of SC chickens in a 4-hr assay. In contrast, the NK cytotoxicity in gut IEL of FP chickens was not detectable until 16 hr after incubation. The ranges of target cell specificity demonstrated by IEL, spleen, thymus and bursa NK cells were similar to one another and, in general, the level of cytotoxicity increased with incubation time. Thymus and bursa NK cell activity of both SC and FP chickens was not detectable in a 4-hr assay but substantial NK cell activity was demonstrated in a 16-hr assay. The results of the present study demonstrate that various lymphoid organs of chickens, such as spleen, thymus, bursa, and gut intraepithelium, contain subpopulations of cells that can mediate spontaneous cytotoxicity.     

Adjuvant treatment of operable stomach cancer with polyadenylic.polyuridylic acid in addition to chemotherapeutic agents. Differential effect on natural killer cell and antibody-dependent cellular cytotoxicity

Peripheral blood lymphocytes of operable stomach cancer patients were evaluated sequentially for their natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) activities before and after chemotherapy in association with polyadenylic.polyuridylic acid [poly(A).poly(U)]. Their cytotoxicity was measured by 4 h-chromium release assays, using human K562 and sensitized murine L1210 cells as targets for assays of NK and ADCC respectively. The mean NK cytotoxicity of 89 patients before treatment was significantly lower than that of the 18 sex- and age-matched healthy controls, whereas assays of ADCC showed similar levels of cytotoxicity in both groups. Patients who had received postoperative chemotherapy (5 fluorouracil, 12 mg/kg and adriamycin, 40 mg/M2) once, had, 5 days after injection, NK cytotoxicity levels similar to those before treatment. For these patients, an additional administration of poly(A).poly(U) (100 mg) resulted, 2 days later, in a significant increase in the levels of NK cytotoxicity without affecting the levels of ADCC. Repeated injections of poly(A).poly(U) alternated with chemotherapy induced, consistently, exclusive enhancement of NK activity after each injection. These results suggest that the effector cells for NK and ADCC activities are of functionally different cell populations.     

Rapid cytokine up-regulation of integrins, complement receptor 1 and HLA-DR on monocytes but not on lymphocytes.

Short-term (3 hr) incubation of whole blood with human recombinant cytokines induced rapid changes in the expression of monocyte but not of lymphocyte surface molecules. The percentage of monocytes bearing CD11b molecules was enhanced by tumour necrosis factor-beta (TNF-beta), whilst that of CD11c was increased by both TNF-alpha and TNF-beta. The mean fluorescence intensity (MFI) of monocyte CD11a was enhanced by interleukin-2 (IL-2), TNF-alpha and TNF-beta, and that of CD11b, CD11c and CD18 was increased by IL-2, IL-4, TNF-alpha and TNF-beta. The proportion of monocytes expressing HLA-DR antigens was not modified by the cytokines investigated, but its MFI was increased by IL-2, IL-4, TNF-alpha and TNF-beta. In contrast, the percentage of monocytes bearing complement receptor 1 (CD35) was enhanced by IL-2, TNF-alpha and TNF-beta but the MFI of this molecule was not modified by these cytokines. The highest up-regulation of CD18, HLA-DR and CD35 was observed with 100 U/ml of either IL-2, IL-4, TNF-alpha or TNF-beta. Decreasing the concentration of all four cytokines from 100 to 10 and 1 U/ml diminished the levels of expression of all molecules, with the exception of CD35, which reached its maximum upon incubation with 1 U/ml of TNF-alpha. IL-1 beta, IL-6 or interferon-gamma (IFN-gamma) did not modify the expression of any of the above monocyte surface determinants. Moreover, none of the lymphocyte surface molecules investigated was modified by 3-hr incubation of blood with cytokines. The demonstration that cytokines selectively and rapidly up-regulate integrins, complement receptor 1 and HLA-DR molecules, on monocytes but not on lymphocytes, suggests that similar mechanisms of mononuclear cell activation by cytokines may control the development and duration of the inflammatory process.     

Antibody-dependent cytotoxicity on chicken red blood cell targets mediated by the U937 cell line.

We have characterized a model system for the study of antibody-dependent cytotoxicity (ADCC) mediated by human macrophages and monocytes. The U937 cell line is used as a source of effector cells. We confirmed a previous report (Gidlund et al., 1981) that U937 can be activated using PMA to kill in ADCC, and the characteristics of the observed cytotoxicity are described. Activation of effectors was maximal after 20-hr preincubation in the presence of 10 ng/ml PMA. In these conditions, lysis was approximately 70% in 2 hr at an effector to target ratio of 5:1. Activation correlated with the expression of complement receptors CR1 and CR3. No antibody-independent cytotoxicity was observed. The effects of various inhibitors of oxygen species were investigated: the lysis obtained in the above conditions was inhibited at 50% in the presence of either 450 mM dimethyl sulphoxide or 30,000 U/ml catalase, but superoxide dismutase (up to 10,000 U/ml) or ferricytochrome c (up to 2 mM) had no effect. The same inhibition was observed with 40 mM desferrioxamine or with 1 mM 0-phenanthroline, which are both iron scavengers, or in the presence of 300 microM colchicine or 1.5 microM dihydrocytochalasin B, which are two inhibitors of cytoskeletal functions. An identical effect was obtained in the presence of 1 TIU/ml bovine pancreas trypsin inhibitor, whereas soya bean trypsin inhibitor, which is more specific, had no effect up to 5000 BAEE U/ml. No inhibition was seen with protein synthesis inhibitors as cycloheximide or puromycin at 40 micrograms/ml. The significance of these results is discussed.     

Reduction by OK-432 of the monolayer contact-mediated inhibition of human natural killer cell activity

In the present study we investigated the effect of OK-432, a streptococcus preparation, on the contact-mediated inhibition of human NK activity by primary cultures of monolayer cells. Either peripheral blood lymphocytes (PBL) or large granular lymphocytes (LGL) were incubated (2 x 10(6) cells/ml, total volume 2 ml) on confluent monolayer cells (uvea-derived fibroblasts, uvea-derived melanoma cells, or renal carcinoma cells) for 18 h in 24-well plates, washed twice, and tested for cytotoxicity against K562, a human myelogenous leukemia cell line, in a 4 h 51Cr-release assay. After contact with monolayer cells, NK activity of both PBL and LGL was significantly reduced. When these effector cells were preincubated with 0.1 U/ml of OK-432 for 18 h and then tested for the sensitivity to contact-mediated inhibition, the inhibition was significantly reduced. The pretreatment of monolayer cells with OK-432 or the addition of OK-432 into the coculture wells (of effector cells and monolayer cells) also significantly reduced the contact-mediated inhibition. Moreover, OK-432 (0.1 U/ml) reestablished the inhibited NK activity of PBL. These results suggest that OK-432 might enable NK cells to escape from the contact-mediated inhibition by monolayer cells and thus provide an additional potential mechanism for the observed clinical effectiveness of OK-432 reported by many groups.     

Interleukin-4 downregulates interleukin-6 production in human peripheral blood mononuclear cells

We report that recombinant human interleukin-4 (IL-4) downregulates interleukin-6 (IL-6) production by human peripheral blood mononuclear cells (PBMC). PBMC were preincubated for up to 24 hr in the presence of IL-4 (100 U/ml) and then activated with lipopolysaccharide B Escherichia coli 026:B6 (LPS, 10 micrograms/ml), recombinant human tumor necrosis factor-alpha (TNF-alpha, 200 U/ml), or Concanavalin A (Con A, 10 micrograms/ml). Although all these signals induced IL-6 production, IL-4-treated cells produced significantly reduced levels of IL-6 protein. This effect was dose and time dependent. We conclude that IL-4 is a potent downregulatory modulator of IL-6 expression in human PBMC.     

Effect of human interleukin-2 from different sources on lymphocyte and airway beta-adrenoceptor function

The effect of recombinant human interleukin-2 (rh IL-2, Genzyme, yeast derived) on the beta-adrenoceptor function of human peripheral blood mononuclear cells (PBMC), guinea pig splenic lymphocytes and isolated guinea pig tracheal spirals was investigated. Rh IL-2 (Genzyme, yeast derived) induces a dose dependent inhibition of the isoprenaline-stimulated cAMP production in PBMC and splenic lymphocytes after a two hour preincubation period. The inhibition is significant at 0.01 U/ml IL-2 and reaches a maximum at 1 U/ml amounting 81 +/- 8% and 76 +/- 6% for human PBMC and guinea pig splenic lymphocytes respectively. The sensitivity of isolated guinea pig tracheal spirals to isoprenaline is also significantly decreased after a two hour preincubation period with 1 U/ml rh IL-2 (Genzyme, yeast derived). In contrast, rh IL-2 (Cetus, bacteria derived) does not affect the beta-adrenoceptor function of human PBMC, guinea pig splenic lymphocytes and isolated tracheal spirals, after a two-hour preincubation period. Furthermore, human cell-line derived IL-2 (Jurkat, Genzyme) also does not influence human PBMC beta-adrenoceptor function. It can therefore be concluded that IL-2 does not affect lymphocyte and airway beta-adrenoceptor function after a two hour preincubation period. The inhibition of beta-adrenoceptor function by yeast derived rh IL-2 (Genzyme) is therefore probably not related to IL-2.     

Natural killer cells in normal pregnancy: analysis using monoclonal antibodies and single-cell cytotoxicity assays.

Peripheral blood lymphocytes (nylon wool non-adherent) from healthy pregnant women and normal non-pregnant females were tested for natural killer (NK) cell-mediated cytotoxicity against K562 target cells both by 51Cr-release assay and single-cell cytotoxicity assay in agarose. The results indicated depression of NK cytotoxicity in pregnancy due to a decrease in the proportion of target-binding lymphocytes as well as a reduction in the lytic capacity of target-bound cells. The ability of active pregnancy-associated NK lymphocytes to recycle appeared to be unimpaired. Analysis of lymphocyte populations with monoclonal antibodies recognizing NK cell-associated antigens showed that the number of Leu-11+ lymphocytes was reduced in pregnancy. Enumeration of Leu-7+ cells and correlation of NK cell subpopulation data with cytotoxicity assay data suggest that pregnancy is associated with a reduction in the number of mature NK cells and probably also an inhibition of post-binding lytic activity.     

Increased natural killer cell cytotoxicity and IL-2 production in recurrent spontaneous abortion

PROBLEM: To determine whether natural killer (NK) cells cytotoxicity in peripheral blood is altered in patients with a history of recurrent spontaneous abortion (RSA); also, if there is any correlation between cytokine production and NK cytotoxicity. METHOD OF STUDY: In this case-control study, 21 patients with RSA within 24 hr of the last abortion (group I), and 32 pregnants with no history of abortion (group II) were surveyed. NK cell cytotoxicity was evaluated by flow cytometry, and IL-2, IL-10, transforming growth factor beta1 were measured in cell culture supernatant by ELISA method. RESULTS: Group I showed higher NK cytotoxicity than group II at all of effector to target (E:T) ratios (P < or = 0.045).The correlation between production of IL-2 and NK cytotoxicity was positively significant (R = 0.350, P = 0.001). Group I had significantly higher levels of IL-2 than group II (P = 0.001). In group II, the production of IL-10 by peripheral blood mononuclear cells was higher than group I (P = 0.002). CONCLUSION: Increased NK cell cytotoxicity and high level of IL-2 may be considered as a risk factor for RSA.     

胸腺因子D对LAK细胞活性诱导的影响

本文报道利用ＭＴＴ法和４小时５１Ｃｒ释放法，在有或无ＩＬ－２存在的情况下，研究了ＴＦＤ对正常人ＰＢＭＣ体外增殖、ＬＡＫ活性诱导的影响。结果表明：单纯ＴＦＤ不能促进静止的淋巴细胞增殖，也不能诱导出高活性的ＬＡＫ细胞，但可促使经ＩＬ－２活化的淋巴细胞进一步增殖如先用ＩＬ－２活化淋巴细胞２４小时，再加入ＴＦＤ联合诱导，第４天时，ＬＡＫ活性可达８１．３±６．５％，明显高于单用ＩＬ－２组（Ｐ＜０．０１）。     

Cytotoxicity on tumour cells of human mononuclear phagocytes: defective tumoricidal capacity of alveolar macrophages.

Human cells of the monocyte-macrophage lineage were isolated by adherence from peripheral blood, peritoneal exudate, non-neoplastic ascites, benign ovarian cystic fluid and bronchoalveolar lavages. Cytolytic activity was measured as 3H-thymidine release from prelabelled mKSA TU5 tumour cells over 48-72 hr and cytostasis was evaluated in a 72-hr spectrophotometric assay. Mononuclear phagocytes from the various anatomical sites examined, except lung alveolar spaces, were significantly cytolytic and cytostatic on target cells. Unlike other cells of the monocyte-macrophage lineage, alveolar macrophages were not cytocidal, but significantly inhibited tumour cell proliferative capacity. Peripheral blood monocytes and peritoneal macrophages showed enhanced cytotoxicity in the presence of partially purified human fibroblast interferon or of lymphokine supernatants from mitogen-stimulated lymphocytes. In contrast, interferon did not affect the cytotoxic potential of alveolar macrophages, whereas lymphokines augmented their cytostatic activity and rendered them weakly cytolytic.