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PubMed1984

Lectin-dependent cell-mediated cytotoxicity: assessment of cytotoxic reactivity following challenge with syngeneic tumors.

Spleen cells from syngeneic tumor-bearing mice were examined for direct cell-mediated cytotoxicity (DCMC) and lectin-dependent cell-mediated cytotoxicity (LDCC). In the DCMC assay specific cytotoxicity against the homologous tumor cell was assessed. In the LDCC assay cytotoxicity was nonspecifically assessed against EL-4 cells in the presence of concanavalin A or phytohemagglutinin. Most tumor lines tested (19/22) produced no cytotoxic reactivity in either the DCMC or LDCC assays. In the case of the remaining tumor lines (EL-4, BW5147-3, and P815 Y-3), significant LDCC, but not DCMC, was detected, which indicated that although cytotoxic effector cells had been activated, the reactivity was not directed toward the homologous tumor cell or could not be expressed in the DCMC assay. The EL-4 and BW5147-3 cell lines proved to be sporadic in terms of their ability to induce LDCC, whereas the P815 Y-3 cell line produced consistent LDCC. Reactivity induced by P815 Y-3 cells appeared to be due to the constitutive production and release of a soluble component which could activate cytotoxic T-cells in vivo.

Animals↗
PubMed1982

Inhibition of monocyte-mediated antibody-dependent cellular cytotoxicity by ouabain: relationship between cytotoxic function, glycolysis, and intracellular cation homeostasis.

Ouabain, a specific inhibitor of membrane Na+K+-ATPase, was used to study the relationship between monovalent cation, homeostasis and cytotoxic effector function. 5 X 10(-6) M ouabain completely inhibited monocyte monovalent cation active transport within 30 min but caused only 50% inhibition of monocyte-mediated antibody-dependent cellular cytotoxicity (MMADCC) in a subsequent 20-hr assay. Longer (6-hr) preincubation of monocytes in ouabain was required for nearly complete inhibition of cytotoxic function. The previously reported augmentation of monocyte glycolysis caused by the sensitizing antiserum was decreased by 71% in 5 X 10(-6) M ouabain, identifying monovalent cation transport as the cellular function utilizing a major portion of the ATP generated by this augmentation of glycolysis. The lag in inhibition of MMADCC indicated, however, that a delayed effect of ouabain (e.g., changes in intracellular [K+] and [Na+]), and not the rapid ouabain inhibition of cation transport, caused inhibition of cytotoxic function. Four additional findings support this interpretation: i) a 30-min preincubation in ouabain caused little inhibition of MMADCC in a 4-hr assay; ii) monocytes lost cytotoxic activity when incubated in medium (0.2 mEq/cytotoxic activity when incubated in medium (0.2 mEq/liter) that reduces intracellular [K+]; iii) the rapid recovery of cytotoxic activity after readjustment of extracellular [K+] to 6 mEq/liter was blocked by ouabain; iv) increasing membrane K+ permeability by valinomycin while blocking active transport by ouabain caused 50% inhibition under conditions in which neither agent alone significantly affected MMADCC. Thus, it is suggested that homeostasis of monocyte intracellular [K+] and [Na+], but not monovalent cation active transport per se, is required for cytotoxic function.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1978

Spontaneous and lectin-dependent cellular cytotoxicity by lymphocyte subpopulations against cell lines susceptible or resistant to spontaneous cytotoxicity.

In the present study we have investigated whether cell lines, which are resistant to spontaneous cytotoxicity, can be killed by lectin-dependent cellular cytotoxicity (LDCC), the expression of EAC (7S) receptors on LDCC effector cells, and the relationship between spontaneous cytotoxicity and LDCC when EAC (7S) receptor-positive or -negative subpopulations are tested against different target cell lines. We found that target cells which are resistant to spontaneous cytotoxicity can, indeed, be killed by LDCC, and that there is an inverse relationship between spontaneous cytotoxicity and LDCC, both when unfractionated lymphocytes were tested against different target cells and when fractionated cells were tested against cell lines highly susceptible to spontaneous cytotoxicity. The implications of these findings, in relation to the relative specificity of the spontaneous cytotoxicity system, are discussed.

Cell Line↗
PubMed2002

Study of diverse mechanisms of cell-mediated cytotoxicity in gene-targeted mice using flow cytometric cytotoxicity assay.

Cytotoxic lymphocytes kill tumor or virus-infected target cells utilizing two mechanisms-(1) release of lytic granules (containing perforin and granzymes), and (2) Fas ligand (FasL)/Fas or TNF-initiated apoptosis. We have examined mechanisms of target cell lysis by effector T cells from gene-targeted and mutant mice using a new Flow Cytometric Cytotoxicity Assay (FC Assay). Target cells were labeled with PKH67 dye. Cell death was estimated by 7-AAD inclusion and annexin V-PE binding. A direct correlation has been found between the percentage of dead target cells in FC Assay and the results of 111In release cytotoxicity assay when effector T cells from either Pfp -/- (perforin knockout) or gld (non-functional Fas Ligand) mice were used. As shown by the 4 h FC assay, the granule-mediated mechanism was utilized by T cells from gld mice. In contrast, T cells from Pfp -/- mice used death receptor-mediated lysis. Therefore, cytotoxic cells from gene-targeted and mutant mice can serve as valuable tools for studying different mechanisms of cell-mediated cytotoxicity, and the FC assay could be applied irrespective of which cytotoxic effector pathway is involved.

Animals↗
PubMed1984

Mechanism of cell-mediated cytotoxicity at the single cell level. VI. Direct assessment of the cytotoxic potential of human peripheral blood non-lytic effector-target cell conjugates.

Single cell cytotoxicity assays reveal that a large percentage of lymphocytes are unable to kill attached targets in a 4- to 18-hr assay. Additional signals (in the form of lectin or anti-target antibody) delivered to target-bound lymphocytes enable these previously non-lytic lymphocytes to kill attached target cells. This finding was obtained by using a modification of the single cell assay, in which lectin or target cell antibody is incorporated into agarose with preformed lymphocyte-target conjugates. Human peripheral blood lymphocytes (PBL) or Percoll density gradient-enriched large granular lymphocytes (LGL) were used as effector cells in natural killer (NK), antibody-dependent cellular cytotoxicity (LDCC) assay systems. The targets used were NK-sensitive K562 and Molt-4 and NK-insensitive Raji. Several findings were made in the modified single cell assay, namely a) the frequency of cytotoxic NK or ADCC effector cells was not augmented, suggesting that the initial trigger was sufficient for lytic expression in these instances. Furthermore, these results showed that the NK-sensitive targets used do not bind nonspecifically to the LDCC effector cells. K562 coated with Con A, however, serve as LDCC targets. b) The frequency of two target conjugate lysis by NK/K effectors was not augmented by Con A. These results suggest that Con A does not potentiate the killing of multiple targets bound to a single cytotoxic lymphocyte. c) Although conjugates formed between LGL or PBL and NK-insensitive Raji are non-lethal, significant lysis was observed when these conjugates were suspended in Con A or antibody agarose. These results demonstrate that Raji bind to cytotoxic NK, K, and LDCC effector cells, but are lysed only when the appropriate trigger is provided. d) The cytotoxic potential of non-lytic conjugates appears to lie within the low density Percoll fraction, although the high density lymphocytes are able to nonlethally bind to targets. Altogether the results demonstrate that target recognition and/or binding by the effector cells is a distinct event from the trigger or lytic process. The implications of these findings are discussed.

Animals↗
PubMed1992

Cytotoxic drug and cytotoxic drug/G-CSF mobilization of peripheral blood stem cells and their use for autografting.

We analysed 99 courses of leukapheresis after the use of cytotoxic drugs or cytotoxic drugs plus G-CSF (cytotoxic/G-CSF) to mobilize peripheral blood stem cells (PBSC) in 68 patients with hematologic or solid malignancies. Mean yields of granulocyte-macrophage progenitor cells (CFU-GM) with cytotoxic/G-CSF mobilization were significantly higher than those with cytotoxic mobilization (18.6 vs 8.40 x 10(4)/kg). The optimal timing of collection was different between these two mobilizations; the mean number of days to a peak level of circulating CFU-GM after cytotoxic/G-CSF mobilization was less than that after cytotoxic mobilization (24.2 vs 27.7 days). The leukocyte level on the day of peak CFU-GM was significantly higher in cytotoxic/G-CSF mobilization than that in cytotoxic mobilization (mean 12.8 vs 2.7 x 10(9)/l), whereas the platelet level was not different (mean 132 vs 125 x 10(9)/l). Increasing patient age was not a major adverse factor for PBSC collection. Synchronous recovery of both leukocytes and platelets was critical for achieving a high CFU-GM yield in these two mobilizations. Following PBSC autotransplantation, the rate of trilineage hematologic reconstitution showed a significant correlation with the infused dose of CFU-GM, whether they were collected with cytotoxic or cytotoxic/G-CSF mobilization. These results suggest that G-CSF can expand the PBSC pool and that CFU-GM yield after cytotoxic/G-CSF mobilization may predict trilineage hemopoietic reconstitution after ABSCT, as well as cytotoxic mobilization.

Adolescent↗
PubMed1996

Chromium- and nickel-induced cytotoxicity in normal and transformed human keratinocytes: an investigation of pharmacological approaches to the prevention of Cr(VI)-induced cytotoxicity.

Chromium and nickel compounds cause irritancy but can also induce allergic contact dermatitis. The aims of this study were to characterize the direct cytotoxic effects of Cr(VI), Cr(III) and Ni(II) salts on keratinocytes, and to investigate pharmacological strategies to protect cells against Cr(VI)-induced cytotoxicity. Normal human keratinocytes and the HaCaT keratinocyte cell line were used. Cell viability was assessed by neutral red dye uptake, the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) eluted stain assay and measurement of lactate dehydrogenase (LDH) activity in the medium. The assays varied slightly in their sensitivities (neutral red > MTT > LDH) although all three gave similar results. In both cell types, the relative order of cytotoxicity of the salts was Cr(VI) >> Ni(II) > Cr(III). There were no major differences between chromium salts of a common valency. Normal human keratinocytes showed a much greater variability in their response to Cr(VI) and Ni(II) salts than HaCaT cells and were generally more resistant to Cr(VI)- and Ni(II)-induced cytotoxicity. Several drugs were screened for their potential to protect both cell types against the cytotoxic effects of Cr(VI), specifically the reducing agents ascorbic acid, cysteine and glutathione, and the Cr(VI) cellular uptake inhibitors 4,4'-diisothiocyanato-2,2'-stilbenedisulphonic acid (DIDS) and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulphonic acid (SITS). All five drugs provided concentration-dependent protection against Cr(VI)-induced cytotoxicity but only ascorbic acid offered complete protection. Several of these pharmacological approaches to the prevention of Cr(VI) cytotoxicity confirm previous clinical studies on the inactivation of Cr(VI), while the clinical potential of others has yet to be investigated.

Ascorbic Acid↗
PubMed1993

CD2/LFA-3 or LFA-1/ICAM-1 but not CD28/B7 interactions can augment cytotoxicity by virus-specific CD8+ cytotoxic T lymphocytes.

It is well established that adhesion molecules are required for interaction between cytotoxic T lymphocytes (CTL) and target cells. Two adhesion pathways, CD2/LFA-3 and LFA-1/ICAM-1 can support cytotoxicity by allospecific CD8+ CTL. In this study, it was investigated whether these adhesion pathways can be utilized independently by influenza virus-specific HLA-A2-restricted CTL clones. It was furthermore examined whether the CD28/B7 pathway can augment virus-specific CTL activity. To this end, seven CD8+ CTL clones were established that were specific for a peptide encompassing positions 59 to 68 (p[59-68]) of the influenza virus matrix protein. These seven clones apparently originated from different precursors, as they utilized different V alpha and V beta or J alpha gene segments. Six of seven clones were able to lyse mouse L cells co-transfected with HLA-A2 and either LFA-3 (LA2/LFA-3) or ICAM-1 (LA2/ICAM-1) in the presence of p[59-68] but did not lyse L cells that expressed only HLA-A2 and peptide. Three of the most cytotoxic clones were selected for further analysis. The cytotoxicity of the clones against LA2/LFA-3 cells was blocked by anti-LFA-3 and anti-CD2 monoclonal antibodies (mAb), while these antibodies did not affect cytotoxicity against LA2/ICAM-1 cells. Likewise, the activity against LA2/ICAM-1 was blocked only by anti-LFA-1 and ICAM-1 mAb. These clones were unable to lyse L cells co-transfected with HLA-A2 and B7, the counter structure of CD28, despite the fact that these clones expressed CD28. These data indicate that CD8+ virus-specific CTL can utilize either the CD2/LFA-3 or the LFA-1/ICAM-1 adhesion pathway. The CD28/B7 pathway seems not to be required for cytotoxicity mediated by activated virus-specific CTL.

Amino Acid Sequence↗
PubMed1993

Mycobacteria induce CD4+ T cells that are cytotoxic and display Th1-like cytokine secretion profile: heterogeneity in cytotoxic activity and cytokine secretion levels.

Protective immunity against mycobacteria is dependent on antigen-specific T cells. Current evidence suggests that not only helper T cells that activate infected macrophages but also cytotoxic T cells (CTL) that lyse infected macrophages are involved in protection. Mycobacterium-specific CD4+ CTL are readily detectable among primary peripheral T cells but what proportion of CD4+ T cells display cytotoxic activity is not known. Whether the cytotoxic CD4+ T cells are identical to or distinct from those that produce interferon (IFN)-gamma is also unknown. In addition, studies on CTL in mycobacterial infections have focused primarily on selected antigens like hsp65 but have not analyzed systematically whether other mycobacterial antigens can activate CTL as well. These issues are relevant not only to a further understanding of protective immunity and immunopathology but also may have implications for the design of effective vaccines. To start addressing these issues, we have studied a large panel of CD4+ T cell clones specific for a broad range of mycobacterial antigens, and analyzed their ability to lyse mycobacterium-pulsed target cells and to release IFN-gamma and interleukin (IL)-4. Our results show that the vast majority of CD4+ T cell clones are able to lyse mycobacterial antigen-pulsed target cells, and that those CTL can be triggered by a wide variety of mycobacterial antigens. CD4+ CTL released high levels of IFN-gamma, but low or nondetectable levels of IL-4. In contrast, control tetanus toxoid-specific T cell clones or lines displayed poor or weak cytotoxic activity and released high levels of IL-4. The antimycobacterial clones appeared to be heterogeneous in their levels of cytotoxic activity and IFN-gamma release. Interestingly one T cell clone was able to lyse only mycobacterium-pulsed macrophages but not B cells suggesting possible selectivity in target cell recognition for some CTL. These in vitro data have to be interpreted with some caution. Nevertheless they confirm and significantly extend previous observations and suggest that mycobacteria preferentially induce CD4+ T helper type 1 (Th1)-like cells that display cytotoxic activity, and release high levels of IFN-gamma but no or little IL-4. The induction of such Th1 like cells is specific for mycobacteria since tetanus toxoid induced T cells that were poorly or not cytolytic and secreted high levels of IL-4.

Antigens, Bacterial↗
PubMed1986

Regulation of the cytotoxic activity of alloreactive cytotoxic T lymphocytes by helper cells and lymphokines.

The cytotoxic activity of alloreactive cytotoxic T lymphocytes (CTL) was maintained and augmented by transferring cells from a 5-day mixed lymphocyte culture MLC into a host culture (HC) containing indomethacin, freshly explanted normal spleen cells, and peritoneal cells which were syngeneic to the MLC cells. The MLC cells used in the transfer experiments were generated by culturing untreated H-2b splenic responders with irradiated H-2d stimulators, or were generated by culturing Lyt-2-depleted H-2b splenic responders with irradiated H-2d stimulators. The allo-CTL were found to be derived from the donor MLC (first culture) when unfractionated MLC cells were transferred into a host (second) culture and incubated for 5 days. In contrast, the allo-CTL were derived from host culture cells when Lyt-2-depleted MLC cells were transferred and the combined cultures incubated for 5 days. In the former case, the augmentation of MLC-derived cytotoxicity did not result from nonspecific expansion of all donor T cells; instead it was mediated by lymphokine(s), distinct from IL-2, produced by helper T cells generated in host culture, which appeared to selectively expand the antigen-specific CTL or to increase the cytotoxic activity of these CTL. The helper T cells were Thy-1+, L3T4+, and Lyt-2-. These findings indicate that antigen-nonspecific help was provided by helper cells or helper factors (lymphokines) generated in the host culture, which maintained and augmented the cytotoxic activity of the fully generated allo-CTL. This helper effect was also seen in the induction of primary allo-CTL responses which could be generated with fewer stimulating cells and with a stronger cytotoxic response at different R/S ratios tested. The generation of allo-CTL in second culture following transfer of Lyt-2-depleted MLC cells to host cultures appears to have involved antigen carryover from the MLC; however, antigen carryover alone was not sufficient. It appears that in the absence of Lyt-2+ suppressor T cells, antigen-specific help might be generated in donor cultures (Lyt-2-depleted MLC) which promoted or recruited the generation of antigen-specific CTL in host culture.

Animals↗
PubMed1999

Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity.

Keratinocyte cytotoxicity is an important component of the immunopathology of photosensitive lupus erythematosus, and antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be an important mechanism by which autoantibodies, especially those specific for SS-A/Ro, can induce keratinocyte damage in models of photosensitive lupus. We provide further evidence that keratinocytes from patients with photosensitive lupus show significantly greater ultraviolet radiation (UVR)-induced cytotoxicity, and that ADCC of these targets is especially enhanced by autologous patient's serum or by anti-SS-A/Ro+ sera. Keratinocytes from normal uninvolved skin of 29 patients with cutaneous lupus erythematosus (LE) were grown in cell culture and tested as targets in cytotoxicity experiments in vitro. Cultured keratinocytes from patients with systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE) showed significantly greater cytotoxicity following UVR treatment than did keratinocytes from normal adult controls or from neonatal foreskins (P < 0.01). The same cultures also showed greater UVR-induced binding of IgG from fractionated anti-SS-A/Ro+ preparations. ADCC experiments were also performed using keratinocytes cultured from patients with SLE, SCLE, discoid lupus erythematosus (DLE), and normal controls. When keratinocytes were incubated in autologous serum plus a standard mononuclear cell effector population, the percentage of ADCC observed was significantly greater in cultures containing keratinocytes and sera from the SLE and SCLE patients (P < 0.001). When cultured keratinocytes were added to different IgG antibody probes, plus standard mononuclear effector populations, greater ADCC was seen using the anti-SS-A/Ro probe and keratinocytes from patients with SLE or SCLE. With normal human neonatal keratinocyte targets, the anti-SS-A/Ro probe induced greater ADCC than that seen with anti-ssDNA or normal human serum. We have shown that keratinocytes from patients with some forms of lupus erythematosus (SLE and SCLE) show greater cytotoxicity in vitro when irradiated with UVR, and greater susceptibility to ADCC whether the antibody source is their own serum or an anti-SS-A/Ro probe.

Adult↗
PubMed1983

Cell-mediated cytotoxicity toward the donor in patients with well-functioning kidney grafts. Possible mechanism of specifically reduced cytotoxic response.

Patients with well-functioning kidney allografts from one-HLA-haplotype--mismatched related donors have strongly reduced donor-specific cell-mediated cytotoxicity 2-10 years after having received their grafts. This could also be demonstrated in secondary in vitro cell-mediated lympholysis (CML). Even though secondary donor-specific CML did not exceed 10% at an effector-to-target cell ratio of 50:1, specific lysis of donor target cells increased significantly with increasing effector cell concentrations. The weak cytotoxicity toward the donor could be enhanced neither through pool-cell stimulation nor by adding exogenous Interleukin 2 (IL-2) during the induction phase. Furthermore, growth factors were produced in the cultures during the induction of cytotoxic cells in concentrations comparable to those of the sibling control. Thus no evidence could be obtained that lack of IL-2 was causing the decreased cytotoxicity in these patients. Our studies indicate that in vivo depletion of cytotoxic cells with high lytic efficiency is probably the reason for the strongly reduced donor-specific cytotoxicity.

Cytotoxicity, Immunologic↗
PubMed1993

Brefeldin A blocks the cytotoxicity of T cell receptor alpha/beta and gamma/delta cytotoxic T lymphocyte clones reacting against human autologous cancer cells.

We studied the effector mechanism of T cell receptor (TCR) alpha/beta- and gamma/delta-type cytotoxic T lymphocyte (CTL) clones that react with human autologous tumor cells. Treatment of tumor cells with a fungal antibacterial reagent, brefeldin A (BFA), resulted in the inhibition of cytotoxicity of an autologous tumor (HST-2)-specific CD8+ TCR alpha/beta-type CTL, TcHST-2. Other anti-metabolites such as chloroquine, cycloheximide and colchicine did not affect the cytotoxicity. The cell-surface antigen expression, including MHC class I molecules, was not influenced by BFA treatment. Furthermore, BFA did not influence the cytotoxicity of lymphokine-activated killer cells and natural killer cells. Since BFA blocks the transport of peptides from endoplasmic reticulum to the Golgi apparatus, the above data suggest that BFA could affect washing out of the peptide fragments from the MHC class I groove. Consequently, target tumor cells were protected from killing by CTL. Moreover, we obtained a CD4-, 8-, TCR gamma/delta-type (V delta 1+) CTL clone, TcHOT, that reacts against an autologous ovarial carcinoma, HOT. BFA could also inhibit this cytotoxicity, and it is likely that different presenting molecules other than MHC class I proteins participate in the cytotoxicity of this TCR gamma/delta-type CTL. These studies suggest that both TCR alpha/beta- and gamma/delta-type CTL may require antigenic peptides that are most likely derived from the BFA-sensitive, intracellular endogenous target proteins.

Brefeldin A↗
PubMed1990

Development of natural killer cytotoxicity during childhood: marked increases in number of natural killer cells with adequate cytotoxic abilities during infancy to early childhood.

The cytotoxicity of natural killer (NK) cells against K562 cells and their responsiveness to interferon-alpha and interleukin 2 (IL-2) were studied throughout childhood using 51Cr-release and single-cell assays. Although NK activity was extremely low in the neonatal period, it almost reached the adult level during 1 to 5 mo of age and remained at that level thereafter. At the single-cell level, the binding, lytic, and recycling abilities were also depressed in the neonatal period, but these abilities improved conspicuously after this period; in particular, the lysis and recycling were at higher levels during 6 mo to 4 y of age. The absolute numbers of circulating cytotoxic NK cells were high during infancy to early childhood: they were 54 +/- 24 (mean +/- SD/mm3) in neonates, 115 +/- 48 in 1- to 5-mo-old infants, 121 +/- 42 in 6- to 12-mo-old infants, 93 +/- 26 in 1- to 4-y-old children, and 42 +/- 16 in adults. Interferon-alpha and IL-2 could enhance NK activity throughout childhood. The IL-2 enhancement was prominent especially in the neonatal period; IL-2 yielded a 2.5-fold increase in the number of cytotoxic cells and improved the recycling to the adult level. At older ages, interferon-alpha and IL-2 yielded 1.4- and 1.9-fold increases in the number of cytotoxic cells, respectively, but did not enhance the recycling. The increased number of NK cells with adequate cytotoxic abilities during infancy to early childhood indicates the predominance of NK immunity during these periods. IL-2 is a cytokine that induces high levels of NK cytotoxicity even in neonates.

Aging↗
PubMed1993

Natural killer cytotoxicity and antibody-dependent cytotoxicity of cells of rat metrial glands.

Cell suspensions of rat metrial gland tissue, containing healthy granulated metrial gland (GMG) cells, were assessed for their ability to lyse natural killer (NK) cell target Yac-1 myeloma cells in a [51Cr]-release cytotoxicity assay. Cytotoxicity indices were found to be low even after in vivo stimulation of NK cytotoxic activity by polyinosilic-cytidilic acid and the addition of interferon to test cultures. It is concluded that cell suspensions of rat metrial gland, and rat GMG cells in particular, do not exhibit NK cytotoxicity. However, when a heat inactivated rabbit anti-Yac-1 serum was added to assay cultures, cytotoxicity indices above background levels were obtained, indicating that rat metrial glands contain cells capable of antibody-dependent cytotoxicity.

Animals↗
PubMed1985

Cytotoxic lymphokines produced by cloned human cytotoxic T lymphocytes. I. Cytotoxins produced by antigen-specific and natural killer-like CTL are dissimilar to classical lymphotoxins.

Several cloned lines of IL 2-dependent human T cells derived from alloantigen, mitogen, or IL 2-stimulated peripheral blood lymphocytes were examined for their surface marker expression, cytolytic activity in a 51Cr-release assay, and capacity to release cytotoxic lymphokines. Thirty cell lines exhibiting either antigen-specific natural killer cell activity or lectin-dependent killer cell function, which expressed either the CD4 or CD8 surface differentiation markers, were capable of producing cytotoxin(s) in response to the lectins phytohemagglutinin and concanavalin A. Cytotoxin activity was detected on the murine L929 target cell in a 16-hr cytotoxicity assay. In contrast, several nonlytic T cell tumor lines failed to produce a soluble cytotoxin. Antibodies capable of neutralizing human alpha-lymphotoxin were completely ineffective in inhibiting the cytotoxin(s) produced by any of the cytotoxic T lymphocytes (CTL) cell lines. Comparative gel filtration and HPLC hydrophobic chromatography of alpha-lymphotoxin and CTL toxin produced by the CTL-830.B2 clone revealed significant differences in their elution profiles. The CTL-produced toxin and alpha-lymphotoxin exhibited similar kinetics of lysis of the L929 target cells, with 50% target cell lysis occurring at 10 hr. These data indicate human CTL produce a cytotoxin(s) antigenically distinct from alpha-lymphotoxin and imply that human cytolytic effector T cells are not the cellular source for the production of human alpha-lymphotoxin. The relationship of alpha-lymphotoxin and CTL toxin production was investigated in unseparated peripheral blood mononuclear cells stimulated with lectins or IL 2 for 1 and 5 days. Anti-alpha-lymphotoxin antibodies were capable of neutralizing only 30 to 50% of the cytotoxic activity in 24-hr supernatants. Cytotoxic activity in supernatants harvested after 120 hr stimulation with PHA or Con A was neutralized 70 to 100%, whereas the toxin(s) released from IL 2-stimulated lymphocytes was only neutralized 30%. These data suggest the observed heterogeneity of cytotoxic lymphokines produced by unseparated mononuclear cells depends in part on the subpopulations of effector cells responding to a given stimulus and the capacity of different subpopulations to produce distinct cytotoxins.

Cell Separation↗
PubMed1979

Deficiency of antibody-dependent cellular cytotoxicity and mitogen-induced cellular cytotoxicity effector cell function in patients with acute myelogenous leukemia in remission.

Patients with acute myelogenous leukemia in remission have pronounced deficiency in antibody-dependent cellular cytotoxicity (ADCC) and mitogen-induced cellular cytotoxicity. The deficiency in ADCC was partly explained by reduction in the number of circulating effector cells (Fc receptor-bearing cells) demonstrable at a time when white blood cell and platelet counts were normal. These cytotoxic functions, as well as the circulating numbers of T-cells and Fc receptor-bearing cells were further decreased by the administration of monthly cycles of combination chemotherapy with 1-beta-D-arabinofuranosylcytosine and 6-thioguanine. Following each cycle of chemotherapy, progressive recovery of these functions occurs during the third and fourth weeks with occasional increases above base line in patients in whom chemotherapy is withheld for longer than five weeks. In selected patients recovery of one cytotoxic function preceded the other, indicating that these functions are mediated by different effector cells. Administration of a single dose of daunomycin i.v. had no effect in either of these cytotoxic functions or in the circulating numbers of lymphocytes. The decrease in ADCC effector cell function induced by phase cycle-specific agents correlated with the level of reactivity exhibited by patients after achieving bone marrow and clinical remission. Patients showing low levels of reactivity postremission experienced highest degree of depression. In two patients, complete abrogation of ADCC effector function was demonstrated with minimal recovery even six weeks after stopping chemotherapy. These findings indicate that effector cells in ADCC and mitogen-induced cellular cytotoxicity are highly susceptible to phase cycle-specific agents, and their recovery takes longer that of other lymphoid and nonlymphoid populations.

Adult↗
PubMed1979

Augmentation of cell-mediated cytotoxicity to a rat lymphoma. I. Stimulation of non-T-cell cytotoxicity in vivo by tumour cells.

The injection of a syngeneic Gross-virus-induced lymphoma into W/Fu rats induced peaks of cytotoxicity in the spleen attributable to non-T cells and T cells 3 and 10 days later, respectively. The conditions required for augmenting the cytotoxicity of the non-T cells in various lymphoid compartments (shown elsewhere to closely resemble NK cells) were analysed using the ip and iv routes of inoculation and a variety of tumour cells including those normally susceptible or resistant to lysis by NK cells in vitro. Using an ip inoculation of W/FuG-1 cells (a tumour susceptible to lysis by NK cells), a short-lived, 3-fold increase in cytotoxicity was observed in the spleen at day 3 and a 5-fold increase in the PEC at day 5. Cytotoxicity in other lymphoid organs remained unchanged. Tumours resistant to lysis by NK cells also stimulated cytotoxicity in the spleen or PEC, although the effect depended on the dose and route of inoculation used, and depression of cytotoxicity was observed under some conditions.

AKR murine leukemia virus↗