Immunomodulatory effects of arginine butyrate

We have studied the effect of arginine butyrate on T cell and macrophage functions. When target cells are treated with this substance, they become resistant to T cell-mediated cytotoxicity, as detected by the chromium assay. In contrast, when effector T cells are treated, the cytotoxicity seems to be augmented. Peritoneal macrophages incubated with butyrate are increasingly adhesive to substrate. After in vivo treatment, spleen derived macrophages show an augmented cytostatic capacity in the presence of L1210 cells and an enhanced phagocytic activity for IgG-coated erythrocytes. To sum up, the overall effects of butyrate salts on different immune functions are somewhat reminiscent of that of interferon. It is likely that these immune effects contribute, at least in part, to explain its antitumor properties observed in grafted tumors in mice.     

Suppression of antitumor immunity by macrophages in spleens of mice bearing a large MOPC-315 tumor

We had shown previously that progression of MOPC-315 plasmacytoma growth is associated with an increase in the percentage of macrophages in the spleen as well as a decrease in the ability of tumor-bearer spleen cells to mount an antitumor cytotoxic response upon in vitro immunization. Here we provide evidence that macrophages in the MOPC-315 tumor-bearer spleen are responsible at least in part for the suppression of the generation of antitumor cytotoxicity. Accordingly, removal of most macrophages by depletion of phagocytic cells or Sephadex G-10-adherent cells from spleens of mice bearing a large tumor resulted in augmented antitumor immune potential. Also, Sephadex G-10-adherent spleen cells from tumor-bearing (but not normal) mice drastically suppressed the in vitro generation of antitumor cytotoxicity by normal spleen cells. The suppressive activity of these adherent cells did not reside in contaminating suppressor T cells, since it was not reduced by treatment with monoclonal anti-Thy 1.2 antibody plus complement. The Sephadex G-10-adherent cell population from the tumor-bearer spleen suppressed the in vitro generation of antitumor cytotoxicity against autochthonous tumor cells but not against allogeneic EL4 tumor cells, and hence the suppression was apparently specific. The suppressive activity of the Sephadex G-10-adherent cell population from tumor-bearer spleens was overcome by treatment of the tumor-bearing mice with a low curative dose of cyclophosphamide. This immunomodulatory effect of a low dose of the drug in overcoming the suppression mediated by the Sephadex G-10-adherent cell population enables the effector arm of the immune system of tumor-bearing mice to cooperate effectively with the drug's tumoricidal activity in tumor eradication.     

Triggering of interferon gamma-primed macrophages by various known complement activators for nonspecific tumor cytotoxicity

Five known complement activators were evaluated for their capacity to directly activate murine macrophages and to trigger activation of lymphokine primed macrophages for nonspecific tumor cytotoxicity. Bacterial lipopolysaccharide (LPS), Lipid A, polyinosinic-polycytidylic acid, cobra venom factor (CVF), and zymosan directly activated macrophages in a dose-dependent fashion at high concentrations. Subactivating concentrations of each of these agents were found to effectively trigger macrophages which were preprimed either by macrophage-activating factor or by murine recombinant interferon gamma for enhanced tumoricidal activity. An Fc receptor blockade with opsonized sheep erythrocytes abrogated LPS-mediated direct activation and triggering of interferon gamma-primed macrophages, but had no inhibitory effect on direct activation or triggering by CVF for nonspecific tumor cytotoxicity. This study characterizes the capacity of a diverse group of known complement activators to serve as second signal triggers for culmination of the activation process of interferon-primed macrophages for nonspecific tumoricidal activity. These findings suggest that complement activators may directly activate macrophages by stimulation of interferon beta production by macrophages for self-priming and, as we have shown, act as self-triggers. The putative role of macrophage-associated complement components in the activation process is discussed.     

Immunologic suppression of carcinogenesis in spontaneously hypertensive rats (SHR) with T cell depression

A strain of spontaneously hypertensive rats (SHR) showed a selective depression of T cell functions brought about by aging. Conversely, this strain had a high NK cell activity as compared to other normal rat strains. This SHR strain was found to be much more sensitive to the carcinogenic activity of low doses of MCA than were WKA rats with normal T cell functions. Allogeneic thymus grafts almost completely restored the T cell functions of SHR, whereas injection of an immunopotentiator, NSP, enhanced NK cell activity and also caused a partial recovering of T cell functions. When immunologic restoration was achieved, generation of killer T cells to syngeneic SMT-5 tumor cells was induced and the cytotoxic activity of NK cells to K-562 cells was also enhanced. But the cytotoxic activity to the SMT-5 cells of NK cells and macrophages from the treated or untreated SHR was not detected. Allogeneic thymus grafts induced a significant transplantation resistance against a syngeneic SMT-5 tumor and injection of NSP enhanced only the survival days of the rats. Allogeneic thymus grafts also significantly suppressed the incidence of tumors induced by MCA, whereas the injection of NSP was not effective in the prevention of tumor development but was effective in prolongation of latency periods. These results support the hypothesis that immune surveillance mediated by T cells is an important mechanism for the control of tumor development.     

Differential effects of Trypanosoma brucei gambiense and Trypanosoma brucei brucei on rat macrophages

Mammalian immune responses to Trypanosoma brucei infection are important to control of the disease. In rats infected with T. brucei gambiense (Wellcome strain; WS) or T. brucei brucei (interleukin-tat 1.4 strain [ILS]), a marked increase in the number of macrophages in the spleen can be observed. However, the functional repercussions related to this expansion are not known. To help uncover the functional significance of macrophages in the context of trypanosome infection, we determined the mRNA levels of genes associated with an increase in macrophage number or macrophage function in WS- and ILS-infected rats and in cultured cells. Specifically, we assayed mRNA levels for macrophage colony stimulating factor (M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), and macrophage migration inhibitory factor (MIF). Upregulation of GM-CSF and MIF mRNA levels was robust in comparison with changes in M-CSF levels in ILS-infected rats. By contrast, upregulation of M-CSF was more robust in WS-infected rats. The phagocytic activity in macrophages harvested from ILS-infected rat spleens, but not WS-infected spleens, was higher than that in macrophages from uninfected rats. These results suggest that macrophages of WS-infected rats change to an immunosuppressive type. However, when WS or ILS is cocultured with spleen macrophages or HS-P cells, a cell line of rat macrophage origin, M-CSF is upregulated relative to GM-CSF and MIF in both cell types. Anemia occurs in ILS-, but not WS-infected, rats. Treatment of spleen macrophages or HS-P cells cocultured with ILS with cobalt chloride, which mimics the effects of anemia-induced hypoxia, led to downregulation of M-CSF mRNA levels, upregulation of GM-CSF and MIF, and an increase in phagocytic activity. However, the effect of cobalt chloride on spleen macrophages and HS-P cells cocultured with WS was restricted. These results suggest that anemia-induced hypoxia in ILS-infected rats stimulates the immune system and activates macrophages.     

Suppression of antitumor immunity by macrophages in spleens of mice bearing a large MOPC-315 tumor

Summary We had shown previously that progression of MOPC-315 plasmacytoma growth is associated with an increase in the percentage of macrophages in the spleen as well as a decrease in the ability of tumor-bearer spleen cells to mount an antitumor cytotoxic response upon in vitro immunization. Here we provide evidence that macrophages in the MOPC-315 tumor-bearer spleen are responsible at least in part for the suppression of the generation of antitumor cytotoxicity. Accordingly, removal of most macrophages by depletion of phagocytic cells or Sephadex G-10-adherent cells from spleens of mice bearing a large tumor resulted in augmented antitumor immune potential. Also, Sephadex G-10-adherent spleen cells from tumor-bearing (but not normal) mice drastically suppressed the in vitro generation of antitumor cytotoxicity by normal spleen cells. The suppressive activity of these adherent cells did not reside in contaminating suppressor T cells, since it was not reduced by treatment with monoclonal anti-Thy 1.2 antibody plus complement. The Sephadex G-10-adherent cell population from the tumor-bearer spleen suppressed the in vitro generation of antitumor cytotoxicity against autochthonous tumor cells but not against allogeneic EL4 tumor cells, and hence the suppression was apparently specific. The suppressive activity of the Sephadex G-10-adherent cell population from tumor-bearer spleens was overcome by treatment of the tumor-bearing mice with a low curative dose of cyclophosphamide. This immunomodulatory effect of a low dose of the drug in overcoming the suppression mediated by the Sephadex G-10-adherent cell population enables the effector arm of the immune system of tumor-bearing mice to cooperate effectively with the drug's tumoricidal activity in tumor eradication.This paper was presented in part at the annual meeting of the American Association of Immunologists, Chicago, Illinois, 10–15 April 1983     

Cortisol response and immune-related effects of Atlantic salmon (Salmo salar Linnaeus) subjected to short- and long-term stress

It is generally considered that stress causes decreased immune function in fish. In this study we examined in Atlantic salmon (Salmo salar Linnaeus) the effects of both short- (a single 15s out of water) and long-term (4 weeks of daily handling 15s out of water) stress on plasma cortisol (free and total) and glucose levels, expression of interleukin-1beta (IL-1beta) and survival of head kidney (HK) macrophages under culture with Aeromonas salmonicida. In the short-term study, samples were collected prior to the application of the stressor, and at 1, 3, 6, 12 and 24h post stress. Free and total plasma cortisol levels and the percentage of free cortisol increased significantly in the stressed group at 1 and 3h post stress. Plasma glucose levels were significantly higher than those of control fish at 1, 3 and 6h post stress. Constitutive expression of IL-1beta in macrophages isolated from head kidneys in stressed fish was significantly higher at 1 and 3h post stress. However, lipopolysaccharide (LPS) stimulated expression of IL-1beta in HK macrophages, exhibited significantly higher fold increases in unstressed fish compared to stressed fish. In the long-term study, with the exception of an increase in plasma glucose levels at 1 week, there were no significant differences in stress parameters between groups. There was a significantly higher constitutive IL-1beta expression in macrophages isolated from stressed fish over the first 2 weeks. At weeks 1, 2 and 3 the magnitude of IL-1beta response of isolated HK macrophages to LPS stimulation was reduced in >90% of the stressed fish. At 4 weeks there was no significant difference in inducible IL-1beta expression between the groups. Macrophages isolated from stressed fish also showed significantly decreased survival when exposed to A. salmonicida. This study shows a clear pattern from repeated handling stress, whereby effects on immune cells begin with increased constitutive expression of IL-1beta, followed by decreased stimulation of leucocytes by extracellular antigen, and finally decreased leukocyte survival when exposed to A. salmonicida. The implications of these changes in the immune system will be discussed with respect to the use of classical indicators of stress to predict possible effects on the immune system of fish.     

Antinociceptive pattern of flavone and its mechanism as tested by formalin assay

Flavone, dextrose and long swim stress exhibited antinociception. Degree of antinociception was greater with long swim stress as compared to flavone or dextrose. Combination of these treatments resulted in potentiation of antinociception. Naloxone (opioid antagonist; 5 mg/kg i.p.) antagonised flavone or long stress induced antinociception showing opioid medicated mechanism, however, failed to reverse the potentiated antinociceptive component recorded in long stressed animals which received flavone and dextrose. Antinociceptive activity of flavone, dextrose and long swim stress which was documented by acetic acid assay has been confirmed in the present study. Role for opioid system in this action has been demonstrated. Therefore, formalin test can also be considered as an useful assay procedure for testing flavonoids. However, like acetic acid assay this assay procedure also has the limitation that it is unable to detect minor changes in the degree of antinociception produced by physiological interventions such as long swim and dextrose.     

Immune cell-derived small extracellular vesicles in cancer treatment

Small extracellular vesicles (sEVs) secreted by most cells carry bioactive macromolecules including proteins, lipids, and nucleic acids for intercellular communication. Given that some immune cell-derived sEVs exhibit anti-cancer properties, these sEVs have received scientific attention for the development of novel anti-cancer immunotherapeutic agents. In this paper, we reviewed the latest advances concerning the biological roles of immune cell-derived sEVs for cancer therapy. sEVs derived from immune cells including dendritic cells (DCs), T cells, natural-killer (NK) cells, and macrophages are good candidates for sEV-based cancer therapy. Besides their role of cancer vaccines, DC-shed sEVs activated cytotoxic lymphocytes and killed tumor cells. sEVs isolated from NK cells and chimeric antigen receptor (CAR) T cells exhibited cytotoxicity against cancer cells. sEVs derived from CD8⁺ T and CD4⁺ T cells inhibited cancer-associated cells in tumor microenvironment (TME) and activated B cells, respectively. M1-macrophage-derived sEVs induced M2 to M1 repolarization and also created a pro-inflammatory environment. Hence, these sEVs, via mono or combination therapy, could be considered in the treatment of cancer patients in the future. In addition, sEVs derived from cytokine-stimulated immune cells or sEV engineering could improve their anti-tumor potency.     

Involvement of NK cells against tumors and parasites

Host resistance against pathogens depends on a complex interplay of innate and adaptive immune mechanisms. Acting as an early line of defence, the immune system includes activation of neutrophils, tissue macrophages, monocytes, dendritic cells, eosinophils and natural killer (NK) cells. NK cells are lymphoid cells that can be activated without previous stimulation and are therefore like macrophages in the first line of defence against tumor cells and a diverse range of pathogens. NK cells mediate significant activity and produce high levels of proinflammatory cytokines in response to infection. Their cytotoxicity production is induced principally by monocyte-, macrophage- and dendritic cell-derived cytokines, but their activation is also believed to be cytokine-mediated. Recognition of infection by NK cells is accomplished by numerous activating and inhibitory receptors on the NK cells' surface that selectively trigger the cytolytic activity in a major histocompability complex-independent manner. NK cells have trypanocidal activity of fibroblast cells and mediate direct destruction of extracellular epimastigote and trypomastigote forms of T. cruzi and T. lewisi in vitro; moreover, they kill plasmodia-infected erythrocytes directly through cell-cell interaction. This review provides a more detailed analysis of how NK cells recognize and respond to parasites and how they mediate cytotoxicity against tumor cells. Also the unique role of NK cells in innate immunity to infection and the relationship between parasites and carcinogenesis are discussed.     

Human recombinant migration inhibitory factor activates human macrophages to kill tumor cells.

A recombinant form of human migration inhibitory factor (rMIF) obtained from COS-1 cells transfected with MIF-specific cDNA is able to activate cultured human peripheral blood monocytes and monocyte-derived macrophages, in a dose-dependent manner to become cytotoxic for tumor cells in vitro. The cytotoxicity exhibited by macrophages treated with rMIF is > or = 30% above that of cells incubated with control supernatants or with media and peaks 72 hr after the addition of tumor targets. rMIF also induces macrophages to produce tumor necrosis factor (TNF-alpha) and interleukin-1 beta (IL-1 beta). These results demonstrate that rMIF is able to modulate macrophage functions and plays a role in cell-mediated immune response.     

Total leukocytes, T cell subpopulation and natural killer (NK) cell activity in rats exposed to restraint stress

Rats were stressed by immobilization for 3 hrs daily for 11 days and either sacrificed immediately after the last stress session (chronic stress group) or allowed to recover for 12 days and then sacrificed (recovery group). After 11 days of stress, leukocytes and lymphocytes were significantly decreased and neutrophils and large granular lymphocytes were markedly increased. The number of total, helper and suppressor T cells was significantly decreased but the percentage of T cells remained unchanged. Natural Killer (NK) cell activity was unaffected. After a 12 day recovery period from stress, the number of leukocytes returned to normal but the percentage of neutrophils was now below baseline whereas the percentages of lymphocytes and large granular lymphocytes had increased significantly. The number and percentage of total T cells and helper T cells was enhanced and NK cell activity tended to be increased. Thus, chronic stress as well as recovery from stress can affect individual components of the cellular immune system quite selectively and differently. In addition, a comparison of the effects of stress seen in this study with healthy rats with those seen under identical conditions in tumor bearing rats shows that stress or recovery from stress can affect the immune system differently in healthy or tumor bearing animals.     

Bursopentin (BP5) from chicken bursa of fabricius attenuates the immune function of dendritic cells

Bursopentine (BP5), a novel pentapeptide isolated from chicken bursa of fabricius, has been proved to have immunomodulatory effects on B and T lymphocytes, anti-oxidative stress on macrophages, and antiproliferation on tumor cells. However, the effects of BP5 on the immune function exhibited by dendritic cells (DCs), which are regarded as a major target for immunomodulators, remain unknown. In this study, we examined the effects of BP5 on the activation and maturation of murine bone marrow-derived DCs. Our results showed that BP5 significantly suppressed the secretion of lipopolysaccharide (LPS)-induced pro-inflammatory (TNF-α, IL-1β, IL-6 and IL-12p70) and anti-inflammatory (IL-10) cytokines by DCs, and this impact was not due to its cytotoxicity. Besides, BP5 reversed the morphological changes and attenuated the expression of phenotypic markers (MHC II, CD40, CD80 and CD86 molecules) in LPS-induced DCs. Furthermore, BP5 restored the decreased FITC-dextran uptake in LPS-treated DCs, arrested the LPS-induced migration of DCs and abrogated the promoting ability of LPS-induced DCs for allogeneic T cell proliferation. These findings show a new immunopharmacological capability of BP5 and provide a novel approach in the prevention and therapy of chronic inflammation and autoimmunity via abolishing the immune function of DCs.     

Functional heterogeneity among peritoneal macrophages: I. Effector cell activity of macrophages against syngeneic and xenogeneic tumor cells

Peritoneal exudate cells from immunized and nonimmunized animals were separated into subpopulations by centrifugation on discontinuous bovine serum albumin (BSA) density gradients. Cells in the several subpopulations were then tested for their cytostatic or cytotoxic activity against syngeneic and xenogeneic tumor cells. Nonimmune macrophages isolated at the 8 to 11% BSA interface were highly inhibitory to the growth of syngeneic and xenogeneic tumor cells during coculture for 24 to 48 hr. A second macrophage subpopulation of heavier density was not as effective in preventing tumor growth and frequently augmented it. Cytotoxic activity against (C58NT) D tumor cells could not be detected with macrophages or subpopulations of macrophages from immune as well as nonimmune animals, as determined by a 4-hr chromium release assay. The cytotoxic activity of the immune peritoneal exudate cells observed by this assay could be accounted for by the small percentage of lymphocytes present.     

Stress and immunological phagocytosis: possible nongenomic action of corticosterone

Some immunological responses triggered by stress can be mediated by corticosterone activity through cytosolic receptors regulating gene expression. There are, however some reports on the possibility of a nongenomic effect of this hormone to explain phenomena observed in a few minutes. We have found that macrophages from mice subjected to 10 min of cold stress (at -15 degrees C) showed a lower phagocytic capacity mediated by Fcgamma-receptors than cells from control animals. Treating mice with glucocorticoid antagonist RU 486 did not block the decrease in phagocytic capacity. This inhibitory effect on phagocytosis was also observed by experiments in vitro with corticosterone in the concentration found in serum after stress, and could not be prevented by RU 486, actinomicyn D or cycloheximide. These results indicate that corticosterone could affect phagocytosis by macrophages through a nongenomic mechanism, and may have physiological implications.     

The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

It has been well established that immune surveillance plays critical roles in preventing the occurrence and progression of tumor. More and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of cancers. Our previous study found that tumor- targeting therapy of anti-HER2/neu mAb is mediated by CD8⁺ T cell responses. However, we found here that enhancement of CD8⁺ T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40, which are strong stimultors for T cell responses, failed to promote the tumor therapeutic effects of anti-HER2/neu mAb. Analysis of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells, especially CD8⁺ T cells, expressed high level of inhibitory co-signaling receptor PD-1. These data suggest that tumor microenvironment is dominated by the immunosuppressive strategies, which thwart anti-tumor immune responses. Therefore, the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvironment in combination with other therapeutic strategies.     

Influence of acute stress on the triiodothyronine (T3) and serotonin content of rat's immune cells

Stress caused by 48 h food and water deprivation provoked significant changes in T3 and serotonin content of lymphocytes. The concentration of these hormones decreased in the last hour of stress. However, 48 h later there was no difference between the hormone content of immune cells of stressed and control animals. Since in earlier experiments three weeks after exposed to stress a significant difference between the control and stressed animals was found, this means that an imprinting-like phenomenon happened with consequences manifested later. The most sensitive cells to acute stress are lymphocytes, however the imprinting influences all types of of the immune cells.     

Effect of ghrelin administration on phagocytic activity in acute cold-restraint stress exposed rats

Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, was identified in the rat stomach. This peptide acts through nitric oxide (NO) by expressing endothelial nitric oxide synthase (eNOS) and down regulating inducible nitric oxide synthase (iNOS) at its gastroproprotective effect against restraint stress induced damage. Recently the ghrelin receptor has also been detected in peripheral systems including immune tissue. We have investigated the possible effect of ghrelin on phagocytic activity of peritoneal macrophages in acute cold-restraint stress (ACRS) exposed rats. The rats were divided into control, stress and ghrelin groups. In ghrelin groups, single dose and three days consecutive dose of ghrelin (20 microg/kg. i.p.) were applied to rats that were exposed to ACRS for 4 h. 1 ml of saline was injected i.p. after ACRS for 3 consecutive days to the rats of the stress groups. Ghrelin administration reduced the increased phagocytic activity induced by ACRS. We conclude that ghrelin exerts an important role at macrophage phagocytic activity in ACRS exposed rats.     

Tumoricidal activity of syngeneic macrophages from melanoma-bearing mice: Changes with progressive tumor growth

Summary Changes in the cytostatic and cytotoxic activity of macrophages from tumor-bearing (TBM) and control mice were studied in a murine model of malignant melanoma. Syngeneic macrophages from TBM were initially noncytotoxic, but became cytotoxic and achieved their maximum destructive ability after 14 days of tumor growth. With continued tumor growth these macrophages either lost or had reduced cytotoxic activity. In contrast, macrophages from the same melanoma-bearing animals were significantly cytostatic at an earlier stage of tumor growth, but with continued melanoma growth these macrophages were no more cytostatic than controls. Moreover, melanomas grew slowly during the time when macrophages were observed to be cytostatic but grew rapidly at those stages when macrophages had a reduced ability to inhibit melanoma DNA synthesis. When these effector cells became cytotoxic melanomas were growing rapidly and changes in cytotoxicity had little effect on tumor mass. Thus, macrophages do not completely suppress melanoma proliferation and, although exhibiting cytotoxicity they were relatively ineffective in controlling a large mass of tumor cells.     

Immune reactivity in SL2 lymphoma-bearing mice compared with SL2-immunized mice

Summary We have studied the rather paradoxical phenomenon of the growth of an antigenic tumor in an immunocomponent host. This phenomenon was studied by comparing (a) the lymphocyte reactivity and (b) the macrophage cytotoxicity, during SL2 growth in DBA/2 mice (SL2-bearing mice) and in DBA/2 mice immunized against SL2 tumor cells (SL2-immune mice). Immune mice rejected a challenge of tumor cells. The immune T-lymphocytes rendered macrophages cytotoxic (arming) and were able to transfer tumor resistance to naive animals. Nonimmunized mice did not reject a challenge of SL2 cells. In these tumor-bearing mice various forms of immune reactivity were tested. Lymphocytes with the capacity to arm macrophages could not be found in the lymphoid organs. However, lymphocytes isolated from the tissue directly surrounding the subcutaneous SL2 tumor could arm macrophages in vitro.Shortly after subcutaneous tumor grafting cytotoxic macrophages were found in the peritoneal cavity. In the serum macrophage arming factors were detected that rendered macrophages cytotoxic in vitro. This cytotoxicity of the peritoneal macrophages and the presence of macrophage arming factors in the serum showed a similar biphasic pattern. The first phase of cytotoxicity between day 3 and 8 after tumor grafting was tumor (SL2) specific. The second phase from day 12 and onwards was not tumor specific. During the first 4 days after SL2 grafting the DBA/2 mice expressed a specific concomitant immunity to a second tumor graft. Then 7 or more days after grafting the first SL2 tumor, the concomitant immunity was nonspecific as the growth of a second SL2 tumor graft and a L5178Y (DBA/2) tumor graft were inhibited. In addition, the immune suppressive activity of serum and lymphocytes was tested. Neither serum nor lymphocytes from SL2-bearing mice suppressed the macrophage arming capacity of SL2 immune lymphocytes. Lymphocytes from tumor-bearing mice did not inhibit the capacity of SL2-immune lymphocytes to transfer resistance to naive animals. On the contrary, lymphocytes obtained from SL2-bearing mice 14 days after SL2 grafting transfered tumor resistance in a Winn-type assay. These data suggest that the growth of an antigenic tumor is due to the inability of the immune system to mount an effective antitumor effector cell population during tumor growth, rather than an immune suppression of the antitumor reactivity, as a limited immune reactivity could be detected in tumor-bearing mice, whereas immune suppression could not be detected.