Scenes from an unlikely marriage: building a corporate culture in biotechnology.
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Biomedical subjects
C S Henney
Publications and source records attributed to C S Henney.
Interleukin 7: effects on early events in lymphopoiesis.
Recently, rapid progress has been made in defining and characterizing those growth factors associated with the major hemopoietic lineages. In contrast, the regulatory factors associated with the commitment and differentiation of precursor cells in the early events of lymphogenesis are much less clearly understood. In this review, Christopher Henney describes the isolation and characterization of one such factor-IL-7-and its effect on early B- and T-cell development.
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Early events in lymphopoiesis: the role of interleukins 1 and 7.
This article summarizes evidence that interleukins 1 and 7 play a critical role in the early stages of lymphopoiesis. IL-1 has been demonstrated to be identical to the growth factor previously termed haemopoietin-1 and appears to cause the growth of haemapoietic stem cells. Interleukin-7, originally described as a pre-B-cell growth factor, also has proliferative activity on T cells. It is proposed that IL-7 acts on lymphoid stem cells.
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The interleukins as lymphocyte growth factors.
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Hematopoietic activities of interleukin 1.
IL-1 is perhaps the most pleiomorphic of the cytokines. Only recently however has it been suspected that IL-1 has effects in stimulating hematopoiesis. Its principal effect in this regard seems to be stimulation of pluripotent stem cells, causing these cells to then respond to lineage-specific growth factors. Thus, although IL-1 does not function directly as a colony stimulating factor, it synergizes with G-CSF, GM-CSF, and IL-3. Indeed, biochemical and serological evidence suggests that IL-1 accounts totally for the biological activity previously termed hemopoietin-1 which has been shown to play a central role in the regulation of hematopoiesis.
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[Studies on NK cell-target interactions].
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Interleukin-2 and the regulation of natural killer activity in cultured cell populations.
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The treatment of induced immune deficiency with interleukin-2.
In vivo generation of alloreactive cytotoxic T lymphocytes (CTL) was found to be inhibited by treatment of mice with either cyclophosphamide or the glucocorticoid, hydrocortisone acetate. The effects of these immunosuppressive agents could be overcome, however, by the in vivo administration of IL-2 from both murine and human sources. Both human IL-2 derived by recombinant DNA techniques as well as the natural protein from mouse and man all reverse the unresponsive state. A single injection of IL-2 was sufficient to reverse the effect of cyclophosphamide treatment, while additional injections with as little as 8 micrograms of protein ablated the steroid-induced suppression. Furthermore, the responder cells generated in vivo following IL-2 therapy were shown to be antigen specific in terms of their lytic capacity. Thus, IL-2 therapy appears to restore the in vivo responsiveness of immunosuppressed recipients to allogeneic tumor cell challenge. These data demonstrate the importance of IL-2 as an immunoregulatory molecule in vivo and suggest its future use as a potent therapeutic.
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Limiting dilution analysis of interleukin 2 and colony-stimulating factor producer cells in normal and autoimmune mice.
MRL/MP lpr-lpr (MRL-lpr) mice spontaneously develop an age-related disease characteristic of human systemic lupus erythematosus (SLE). Old MRL-lpr mice (4 mo of age) develop antibodies to nucleic acids, display immune complex glomerulonephritis, and have a massive T cell-associated lymphadenopathy. In concert with disease development is data showing an age-related loss of interleukin 2 (IL 2) production by mitogen-stimulated lymphoid cells from these mice. The loss of IL 2 production has been suggested to be involved in the onset and/or development of autoimmune disease seen in these animals. In this report, we examined the frequency of both IL 2 and colony-stimulating factor (CSF) producer T cells in the MRL-lpr mouse by using a limiting dilution analysis assay. Our results show that the number of IL 2 and CSF producer cells present in autoimmune animals is similar to the number found in normal control mice. In addition, IL 2 and CSF producer T cells from autoimmune MRL-lpr mice make similar levels of lymphokine activity, as do producer T cells from normal mice. Our data argue against the previously hypothesized role that a paucity of IL 2 production may be involved in the etiology of autoimmune disease.
Aging↗
Interleukin 2 administered in vivo induces the growth of cultured T cells in vivo.
The capacity of exogenous IL 2 to induce the growth of antigen-activated T lymphocytes in vivo was evaluated. The in vivo growth of adoptively transferred T lymphocytes that had been previously cultured long-term with IL 2 was initially examined, because in vitro such T cells are exquisitely dependent upon exogenous IL 2 for proliferation and survival. Daily administration of IL 2 in vivo, beginning on the day of cell transfer, induced these IL 2-dependent long-term cultured T lymphocytes to proliferate in vivo, and the magnitude of in vivo growth was proportional to the dose of IL 2 administered. The capacity of IL 2 to induce the in vivo growth of antigen-activated T cells not previously exposed in vitro to exogenous IL 2 was similarly studied. T lymphocytes from the spleens of immune mice, activated by 5-day culture with tumor antigen before transfer, survived poorly in vivo when injected with antigen alone, but demonstrated marked proliferation in vivo in response to antigen and exogenous IL 2. By contrast, immune spleen cells transferred with antigen, but without prior culture, proliferated without supplementary exogenous IL 2. Moreover, the growth of noncultured donor T cells was not augmented by the administration of exogenous IL 2, implying that noncultured spleen cells immune to tumor antigens can produce sufficient amounts of endogenous IL 2 in vivo to sustain maximal T cell growth over the time period examined. Importantly, the ability of exogenous IL 2 to induce donor T cell growth in vivo correlated with its ability to function in vivo to augment the anti-tumor efficacy of specifically immune donor T cells in models for the adoptive therapy of disseminated antigenic murine leukemia. Thus, the current studies highlight the potential of exogenous IL 2 to induce T cell growth in vivo and suggest that the administration of IL 2 in vivo may be useful for augmenting T cell responses that are relatively deficient in the production of endogenous IL 2.
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The mechanism of augmentation of natural killer cell activity by syngeneic tumor cells: role of macrophage-derived factor in NK boosting.
The role of natural killer (NK) cells in controlling tumor growth was investigated using an NK-susceptible (c127v-IC2) and an NK-insusceptible (c127av) subline of the lymphoma L5178Y. Syngeneic DBA/2 mice inoculated intraperitoneally with c127v-IC2 tumor cells survived significantly longer than did c127av-bearing mice. Similarly, c127v-IC2, but not c127av tumor cells, were found to augment NK activity of spleen and peritoneal exudate cells in both DBA/2 and BALB/c nu/nu mice when inoculated into the peritoneal cavity. C127v-IC2 tumor cells incubated with either DBA/2 or BALB/c nu/nu spleen cells in vitro boosted NK activity and induced the production of gamma-type interferon (IFN), whereas incubation with c127av tumor cells induced neither NK activity nor IFN. Two kinds of cells cooperated in the production of IFN in response to c127v-IC2 tumor cells, namely, cells which were nonadherent, bore asialo-GM1, NK-1.2 and a low level of Thy-1.2 antigen and thus closely resembled NK cells, and those which were adherent and phagocytic and lacked both asialo-GM1 and NK-1.2 markers, presumably macrophages. Further analysis strongly suggested that c127-v-IC2 tumor cells stimulate macrophages to produce factor(s) which can induce the production of IFN by NK cells. The induced IFN was shown to be of the gamma type by its lability at pH 2.0 and insusceptibility to anti-IFN alpha, beta serum. This suggests a novel pathway for NK cell activation, and strongly supports the importance of macrophages and NK cells in natural resistance against certain tumors.
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Lymphokine-driven "differentiation" of cytotoxic T-cell clones into cells with NK-like specificity: correlations with display of membrane macromolecules.
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Animals↗
Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells.
Interleukin 2 (IL 2) has been shown to be a potent stimulator of natural killer (NK) cells. In the present studies, partially purified mouse and human IL 2 preparations were also found to induce interferon (IFN) from mouse spleen cells. By the criteria of sensitivity to treatment at pH 2 and failure to be neutralized by a potent anti-alpha, beta IFN serum, the species of IFN produced was of type gamma. Cooperation between two types of cell, a macrophage and an NK-like cell, was required for IFN production by murine spleen cells treated with IL 2. The requirement for macrophages could be replaced with supernatant obtained by incubating macrophages for 24 hr with lymphokine preparations containing IL 2. Interestingly, mature T cells apparently played no role in the process. Furthermore, the beige (bg/bg) mutation, which severely impairs NK cell lytic activity, had no effect on the ability of NK-like cells to participate in IFN production. Cell fractionation experiments revealed no dissociation between the requirements for augmentation of NK cytotoxic activity and for IFN production, and it is concluded that at least a portion of the NK boosting induced by IL 2-containing preparations is mediated through gamma-IFN.
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In vivo interleukin 2 administration augments the generation of alloreactive cytolytic T lymphocytes and resident natural killer cells.
Interleukin 2 (IL 2) is a T cell growth factor that has been shown to modulate several in vitro immune responses. Produced by T cells, the lymphokine has been highly purified and used in a series of in vivo studies to examine the effect of IL 2 on murine cytotoxic T cell (CTL) and natural killer (NK) cell reactivity. By employing an immunization protocol known to generate CTL activity against allogeneic tumors, in vivo administration of highly purified IL 2, either in concert, with or 2 days after, tumor administration, resulted in an augmented CTL response as compared to effector cells harvested from untreated, alloimmunized control animals. Characterization of the effector cells responsible for the augmented cytolytic activity showed them to be of the T cell lineage and to be specific for the appropriate immunizing tumor cell. Furthermore, we were able to demonstrate that administration of purified IL 2 to naive, non-antigen-challenged recipients resulted in substantial potentiation of NK cell activity. The augmented cytolytic reactivity was mediated by NK cells as evidenced by effector cell lysis of NK-susceptible but not NK-insusceptible tumor targets. The results of these studies suggest IL 2 functions in vivo as an immune response regulator and may have a beneficial effect as an in vivo immunopotentiator.
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The presence of NK alloantigens on cloned cytotoxic T lymphocytes.
A panel of sera raised against NK-1.1 and NK-2.1 alloantigens was tested for reactivity against a panel of cloned antigen-dependent CTL lines. By using indirect immunofluorescence and flow cytofluorimetry, weak, but clear and consistent, reactivity was found on all CTL. Concordant with the genetics of NK alloantigens, C57BL/6-derived clones were reactive with anti-NK-1.1 and anti-NK-2.1 sera, whereas CBA-derived clones were reactive with anti-NK-2.1 sera but not with anti-NK-1.1 sera. Cloned CTL lines were also able to partially and specifically absorb the antibodies from NK alloantiserum that reacted with splenic NK cells. These results indicate that cloned CTL lines express at least some of the NK alloantigen determinants present on splenic NK cells and have important implications regarding the relationship of CTL and NK cells.
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Interleukin 2 is not sufficient for the continuous growth of cloned NK-like cytotoxic cell lines.
Interleukin 2 (IL 2) has been strongly implicated as the agent responsible for the continuous growth of T cell lines in vitro. In the present study we confirmed that IL 2 alone could support the growth of a widely used cytotoxic T cell line. In contrast, we found that IL 2 was not sufficient to support the long-term growth of cloned NK-like cytotoxic lymphocyte cell lines. Whereas such lines would grow indefinitely in concanavalin A-induced mouse spleen cell supernatant, they would only grow for short periods (2 to 3 days) in the IL 2-containing supernatant of phytohemagglutinin-stimulated LBRM-33 tumor cells, or in IL 2 partially purified from spleen cell or LBRM-33 supernatants. The addition of concanavalin-A or interferon (type beta or gamma) to these supernatants did not improve growth. By contrast, the NK-like cells proliferated equally well in a short-term (24-hr) assay, irrespective of the source of IL 2 (spleen or LBRM-33 supernatant, or partially purified IL 2). Furthermore, the NK-like cells readily depleted IL 2 from the medium, either during growth at 37 degrees C or by absorption at 4 degrees C. It is concluded that at least some cytotoxic cell lines require both IL 2 and other, as yet unidentified, spleen cell-derived factors for long-term growth.
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Selective depletion of NK cell activity in vivo and its effect on the growth of NK-sensitive and NK-resistant tumor cell variants.
Intravenous injection of rabbit anti-asialo-GM1 serum, an antiserum previouslY shown to eliminate splenic natural killer (NK) activity in vitro, profoundly depressed NK activity in CBA, DBA/2 and BALB/c nu/nu mice. The effect on NK activity was selective, as treatment of mice with anti-asialo-GM1 serum did not affect the development of other cytotoxic cells including cytotoxic macrophages following injection of poly I:C, or cytotoxic T cells in response to allogeneic cells. The role of NK cells in controlling tumor cell growth was investigated using an NK-sensitive (cl 27v-1C2) and an NK-resistant (cl 27av) subline of the murine lymphoma L5178Y. Initial studies showed that cl 27v-1C2 cells were at least 100 times less tumorigenic than were cl 27av cells in both syngeneic DBA/2 mice and BALB/c nu/nu mice. In addition, treatment of DBA/2 mice with poly I:C, which boosted NK activity, markedly depressed the growth of cl 27v-1C2 cells, but not of cl 27av cells. On the other hand, treatment of DBA/2 mice and BALB/c nu/nu mice with anti-asialo-GM1 serum led to a marked increase in tumorigenicity of cl 27v 1C2 cells, but had no effect on the tumorigenicity of cl 27av cells. In addition, the protection against cl 27v-1C2 growth afforded by poly-I:C treatment was abrogated by injection oif anti-asialo-GM1 serum. The possibility that the effects observed were caused by binding of the injected antibodies to the tumor cells was minimized by: (1) using a clone of tumor cells (cl 27v-1C2) that lacks chemically detectable asialo-GM1, and (2) pretreating animals with anti-asialo-GM1 rather than administering antiserum and tumor cells concurrently. These studies provided compelling evidence that NK cells could play an active role in controlling tumor growth. Selective depletion of NK activity by injection of anti-asialo-GM1 serum is a method which would be generally applicable to studying the role of NK cells in disease processes.
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