Effects of cyclic AMP on in vivo cytotoxic T lymphocytes generation

Chronic schistosomiasis mansoni is associated with a modulation of schistosome egg-associated cell-mediated granuloma formation. In this study the injection of a cell-free sonicate from either spleen or thymus cells from chronic Schistosoma mansoni-infected mice (> 15 weeks) passively modulated granuloma size in acutely infected (6–8 weeks) syngeneic mice. Cell-free sonicates from age-matched uninfected mice did not suppress granuloma formation. The chronic extracts also suppressed the soluble schistosome egg antigenic preparation-elicited delayed skin test reactivity in 7–8 week infected animals, but failed to suppress the unrelated antigen-elicited reactivity to bovine serum albumin (BSA) of BSA-sensitized animals.     

Induction of granuloma modulation in murine schistosomiasis mansoni by enteric exposure to schistosome eggs

Enteric administration of antigen can induce systemic tolerance. In murine schistosomiasis mansoni, blood flukes produce eggs which enter the intestine. An immunologic phenomenon associated with this disease is a spontaneous diminution in the intensity of the granulomatous response in the liver, lungs, and colonic mucosa with chronic infection, which is termed modulation. It was determined whether modulation of liver granulomas could be induced by enteric immunization with schistosome eggs. Mice infected for 4 wk were immunized by injection of 25,000 eggs into cecal pouches. This induced modulation of liver granulomas by the eighth week of infection. Neither cecal injection of normal saline nor i.p. or subcutaneous injection of eggs could induce the modulatory process. Modulation could be adoptively transferred from enterically immunized donors by injection of spleen cells into infected recipients or into uninfected recipients with synchronous liver granulomas induced by the hepatic embolization of schistosome eggs. Spleen cells treated with anti-Thy-1.2 or anti-Lyt-1.1 and complement could no longer adoptively transfer modulation. These data show that enteric immunization with schistosome eggs can induce modulation of the liver granuloma by a cellular mechanism similar to that described for the natural infection.     

The evolution of immunosuppressive cell populations in experimental mycobacterial infection.

Immunosuppressor activity of considerable potency and complexity was generated during the course of chronic, progressive infection of C3H/Anf mice by Mycobacterium lepraemurium. From the 5th through 10th week after inoculation, spleen cells from infected mice mildly but reproducibly suppressed the direct plaque-forming cell response of normal spleen cell cultures to sheep erythrocytes. Suppression at this stage of infection was mediated by cells with macrophage-like characteristics. A marked increase in splenic suppressor activity at 10 to 11 weeks was associated with the appearance of a second suppressor cell subpopulation composed of T lymphocytes. The appearance of these cells was closely related in time to the onset of rapid splenic enlargement and a loss of cutaneous delayed type hypersensitivity to antigens of M. lepraemurium in mice at 10 to 11 weeks of infection. Suppressor cells were not present in peripheral lymph nodes until terminal infection at 22 to 25 weeks. Suppressor spleen cells depressed the T-dependent antibody response most severely, but there was also a direct effect upon B cells as shown by moderate suppression of responses to TNP-LPS and DNP-Ficoll. Spleen cells from 14-week-infected mice generated a soluble suppressor factor(s) that induces depression of moderate severity, however, the immunosuppression by intact cells was far greater.     

Modulation of granulomatous hypersensitivity. I. Characterization of T lymphocytes involved in the adoptive suppression of granuloma formation in Schistosoma mansoni-infected mice.

The cellular basis of the spontaneous modulation of the granulomatous response to schistosome eggs was analyzed in mice infected with Schistosoma mansoni. Spleen cells of 20 or 32 week-infected mice undergoing modulation, when transferred to 6 week-infected recipients, suppressed the maximal granulomatous response at 8 weeks. Suppression of both naturally forming asynchronous liver and synchronously induced lung lesions was achieved. Specificity of this effect was demonstrated by the suppression of egg granulomas but not antigen-coated bead granulomas developing simultaneously in the lungs of cell recipients. Further characterization showed that suppression was abrogated by pretreating transferred cells with either anti-Thy 1.2 or anti-Iak alloantisera and C. Transfer of macrophage-depleted or fractionated T and B spleen cells confirmed that T cells alone transferred suppression. Moreover, an Ia antigen-bearing (Ia+) subpopulation of T cells was required in the transferred suppression. Moreover, an Ia antigen-bearing (Ia+) subpopulation of T cells was required in the transferred population. An examination of T cells obtained from isolated, dispersed lung granulomas from control and adoptively suppressed mice revealed an increased proportion of Ia+ cells in the latter. It is suggested that Ia+ T cells may be involved in the local modulation of the granulomatous response.     

Eosinophils and immune mechanisms. VI. The synergistic combination of granulocyte-macrophage colony-stimulating factor and IL-5 accounts for eosinophil-stimulation promoter activity in Schistosoma mansoni-infected mice

Eosinophil stimulation promoter (ESP) is a lymphokine activity that stimulates eosinophil migration and is produced by mitogen or specific Ag stimulation of spleen cells from mice infected with Schistosoma mansoni. It is also produced by intact, schistosome egg-induced granulomas isolated from the livers of such mice without additional antigenic exposure. The production of ESP activity is decreased during chronic infection in a time course coordinate with granuloma modulation. Characterization of ESP was pursued to determine its relationship to other cytokines and to identify factors that may play a role in granuloma formation and modulation. Chromatographic separations, assays of recombinant cytokines, and cytokine-specific immunodepletions were used in the characterization. ESP+ supernatant fluids contain both granulocyte-macrophage CSF and IL-5. The removal of both granulocyte-macrophage CSF and IL-5 is required to eliminate ESP activity, and together they act synergistically to constitute ESP.     

Regulatory mechanism of delayed-type hypersensitivity in mice. I. Properties of memory cpells and suppressor cells for delayed-type hypersensitivity against ovalbumin.

Delayed-type hypersensitivity (DTH) response in mice induced by sc injection of alum-absorbed ovalbumin (OA) was accelerated and enhanced by priming sc with a low dose of urea-denatured ovalbumin (UD-OA), 2 or more days earlier, whereas it was suppressed by priming sc with a high dose of UD-OA, 0 or more days earlier. The ability in primed mice to accelerate or suppress the DTH response could be transferred antigen specifically into cyclophosphamide (CY)-pretreated recipients or normal recipients by spleen cells from primed mice, but not by the T-cell-depleted spleen cells. Furthermore, the ability of spleen cells to transfer the acceleration or the suppression appeared transiently around 7 or 4 days after priming, although the acceleration or the suppression in donor mice persisted for a much longer time. Pretreatment with CY abolished the suppression of DTH response in high dose-primed mice and resulted in the acceleration of DTH response. These results suggest that the activity of DTH-related memory T cells which accelerate and enhance the response can be inhibited by suppressor T cells for the DTH response.     

Inhibition of specific immune responses by feeding protein antigens. V. Induction of the tolerant state in the absence of specific suppressor T cells

The effect of CY pretreatment on the ability of OVA feeding to induce both tolerance and active suppression was examined in mice. CY-pretreated, OVA fed mice were fully unresponsive in both OVA-specific DTH and antibody responses, but, in contrast to untreated OVA-fed mice, did not transfer suppression to normal recipients via splenic lymphocytes. Restoration of Ts activity in CY-pretreated mice was accomplished by reconstitution with normal T cells before antigen feeding, indicating that the CY effect was at the Ts precursor level. In addition, it was found that certain OVA-specific immune parameters (DTH and splenic PFC responses) in recipient mice were susceptible to suppression by transfer of spleen cells from OVA-fed donors, whereas other measures (antigen-induced T cell proliferation and serum antibody titers) were not. The data suggest that CY-sensitive Ts are not necessary for either induction or maintenance of specific tolerance after OVA feeding.     

Studies of thymopoietin pentapeptide (TP5) on experimental tumors: I. TP5 relieves immunosuppression in tumor-bearing mice

The allogeneic and syngeneic immune responses of tumor-bearing mice (C57BL/6 mice bearing 3LL and DBA mice bearing P815) were evaluated by the cytotoxic lymphocyte precursor unit (CLP-U) and MLC. In general, tumor-bearing mice showed slightly enhanced immune responses 4 days after tumor inoculation. This enhanced immune response rapidly declined and about 7–10 days after tumor inoculation, both allogeneic and syngeneic responses were markedly lower than normal. Mice treated with TP5, starting 2 weeks before tumor inoculation, retained normal or enhanced allogeneic and syngeneic responses up to 3 weeks after tumor inoculation. When this tumor-induced suppressive effect was studied in cell transfer experiments, spleen cells from tumor-bearing mice enhanced the growth of tumors in syngeneic recipients whereas spleen cells from TP5-treated mice inhibited the growth of tumors in syngeneic recipients. Moreover, the spleen cells from TP5-treated mice also showed enhanced cytotoxic activity against tumor cells in vitro. These findings suggest that the tumors, after a transient stimulatory phase, induced immune suppressive mechanisms in the hosts' immune defenses. Treatment with TP5 prevented the development of these immune suppressive effects and spleen cells from TP5-treated tumor-bearing mice inhibited tumor growth in freshly tumor-inoculated recipients.     

Suppression of delayed hypersensitivity in mice receiving a massive dose of xenogeneic erythrocytes]

The injection of 6x109 sheep red blood cells to mice suppresses delayed-type hypersensitivity (DTH) in situ and activates spleen cells which prevent sensitization of recipients. Preliminary thymectomy of donors and the treatment of cell suspensions with anti-T-globulin abolish suppression of DTH. Pretreatment of mice with low doses of cyclophosphamide (CY) enhances antibody formation and DTH. Higher doses of CY increase the DTH reaction but inhibit antibody formation. The data obtained allow to conclude that suppression of DTH is due to the activity of short-living, intensively proliferating cells of thymic origin and possibly to B cells.     

Specific suppression of the immune response by HGG tolerant spleen cells. I. Parameters affecting the level of suppression.

After adoptive transfer, the spleen cells from mice made tolerant to human gamma-globulin (HGG) specifically suppress the immune response of normal spleen cells. However, this suppressive activity in the spleen cells of tolerant mice is only present for a brief period after treatment with tolerogen. Spleen cells from animals injected 10 days earlier with tolerogen reduce the immune response of an equal number of normal spleen cells by 75%. Spleen cells from mice made tolerant 40 days previously are, however, no longer suppressive, even though they remain completely unresponsive. These data suggest that active suppression of antigen-reactive cells is not the mechanism responsible for maintaining tolerance to HGG, but rather is only transiently associated with the tolerant state. Further evidence in favor of the separation of the tolerant state from suppressive activity is that complete suppression of the normal spleen cell response requires either a high ratio of tolerant to immune competent cells or a delay in the antigenic challenge of the reconstituted recipients. By contrast, such manipulations are not required to demonstrate the complete unresponsiveness of the tolerant cells after adoptive transfer.     

Suppressor T cells induced by soluble immune complexes can adoptively transfer inhibition of cytophilic antibody receptors on macrophages.

Immune complexes (soluble antigens of L1210 and antibody to L1210) when given to allogeneic C3H mice generated suppressor cells that inhibited receptors for cytophilic antibody on macrophages. Thymocytes or nylon-nonadherent splenic T cells (4 × 10⁷) from immune-complex-treated mice transferred this suppressive activity when injected into normal syngeneic mice. Maximal suppression of macrophages occurred 4 to 6 days after transfer. In contrast, even 5 × 10⁷ nylon-adherent, non-T spleen cells from immune-complex-treated (“suppressed”) mice failed to induce macrophage suppression in the syngeneic recipients. When T-cell-depleted “B” mice were used as recipients, neither thymocytes nor splenic T cells from suppressed mice were able to transfer suppressive activity. However, the admixture of 2 × 10⁷ normal syngeneic thymocytes with 4 × 10⁷ thymocytes from suppressed mice restored the latter's ability to elicit suppression of macrophages in T-cell-deprived recipients. Peritoneal monocytes from recipients of suppressor thymocytes (to L1210) could not attach cytophilic antibody to L1210 but could attach cytophilic antibody to EL-4 and sheep erythrocytes. Thus, suppressor T cells induced by immune complexes can transfer immunologically specific macrophage suppression (inhibition of cytophilic antibody receptors) to syngeneic recipients. The suppressor cells required the cooperation of normal T cells, suggesting either recruitment of suppressor cells from, or a helper effect by, the normal T cells, in order to produce their effect.     

Immunoregulation in experimental schistosomiasis: in vitro induction and assay of spleen cell suppressor activity

Spleen cells from normal CBA/J mice or mice infected with Schistosoma mansoni were exposed for 48 to 72 hr to either concanavalin A (Con A), soluble egg antigen (SEA), or soluble worm antigenic preparation (SWAP), treated with mitomycin C to prevent further DNA synthesis, and admixed with either normal or sensitized syngeneic spleen cells exposed to a concentration gradient of phytohemagglutinin (PHA) or SEA, respectively. Both nonspecific (by Con A) and "antigen-specific" (by SEA and SWAP in infected mice only) induction of suppression was observed when using PHA-induced blastogenesis as the final assay. The number of mice with inducible splenic suppressive activity and the degree of PHA suppression induced by exposure to SEA appeared to decline between 8 and 20 weeks of infection. In contrast, when the response of spleen cells from mice infected for 8 weeks to SEA served as the final assay, strong suppressive activity was induced from the spleen cells of all chronically infected mice (20 weeks of infection). This model permits parallel analysis of the induction of suppressor activity by nonspecific and schistosome antigen-specific signals during the course of this chronic, immunoregulated condition, schistosomiasis mansoni.     

T-cell depletion by monoclonal antibodies does not prevent granuloma formation in mice

Effects of T-cell depletion on the formation of organized granulomas in mouse skin were investigated. Monoclonal antibodies (MoAbs) to L3T4 and Lyt-2.2 were injected into euthymic BALB/c mice in order to deplete both T-helper and T-suppressor cell populations. Four days after injection, hepatic schistosome egg granulomas were transplanted into the skin. Injection of MoAbs to L3T4 and Lyt-2.2 was repeated in the recipient mice 6 days later. At the time of transplantation, flow cytometric analysis showed that the number of T cells which were positively stained with surface markers decreased on average by 68% in both regional lymph nodes and spleen. The mitogen response of spleen cells was also markedly reduced. Despite their immunosuppressed condition, development of organized granulomas was observed in the skin of recipient mice by light and electron microscopy 3 weeks after transplantation. The findings indicate that T-cell function may not be essential for initiation of organized granuloma formation.     

Specific, transient suppression of the immune response by HGG tolerant spleen cells. II. Effector cells and target cells.

In a previous report, it was shown that spleen cells from mice made tolerant to human gamma-globulin (HGG)5 could specifically inhibit the immune response of normal spleen cells after adoptive transfer to lethally irradiated recipients. However, that report also showed that the suppressive activity was only transiently associated with tolerant spleen cell populations. It was concluded from those experiments that while suppressive activity could be demonstrated in tolerant spleen cells under certain conditions, such activity was not obligatory for the maintainance of the tolerant state. The experiments presented here were performed to determine the nature of the effector cell(s) and the target cell(s) involved in this system of suppression of the immune response. Treatment of cells from tolerant animals with anti-thymocyte serum and complement to remove thymus-derived (T) cells completely abrogated suppresive activity. Removal of adherent cells from tolerant spleen cells by passage over glass wool columns resulted in partial loss of the suppression. The inhibitory activity of the suppressor cells was resistant to 900 R irradiation regardless of whether the tolerant spleen cells were irradiated before or after adoptive transfer. The cellular target(s) for the supprssor cells was examined by using lipopolysaccharide (LPS) as an alternative source of helper activity for the response to HGG. LPS, injected at the time of the initial antigenic challenge of mice that had been reconstituted with tolerant and normal spleen cells, prevented the expression of suppression against bone marrow-derived (B) cells. However, when LPS was presented only at the time of secondary antigenic challenge, it was unable to overcome suppression of the immune response of reconstituted recipients. Thus, LPS could produce a state where the B cells were resistant to suppression, but LPS could not rescue the responsiveness of B cells once the cells in the reconstituted recipient had been suppressed. In addition, the immune response to both the hapten dinitrophenol (DNP) and the carrier (HGG) were suppressed when recipients of tolerant and normal spleen cells were challenged with DNP6HGG. This indicates that T helper cells are also a target for suppression. The results presented in this paper are discussed in relation to a possible mechanism of suppression which proposes that suppressive activity represents the induction of tolerance in immunologically competent cells by HCG which is closely associated with the tolerant spleen cells.     

Immune response to levan. II. T independence of suppression of cross-reactive idiotypes by anti-idiotype antibodies.

Pretreatment of BALB/c mice with antisera to a cross-reactive idiotype (E109IdX) expressed on many anti-bacterial levan (BL) and anti-inulin (Inu) antibodies leads to a prolonged suppression in production of IdX-bearing molecules in response to BL immunization. There is a comparable suppression in numbers of plaque-forming cells secreting IdX-bearing anti-BL and anti-Inu molecules. Furthermore, spleen cells from anti-E109IdX pretreated mice are unable to transfer to irradiated recipients the ability to produce IdX-bearing anti-BL and anti-Inu antibodies. These results indicate that the suppressive effect is at the precursor level and not simply a clearance of antibodies bearing the IdX. Suppression of IdX production can be achieved by pretreating nu/nu BALB/c mice with anti-E109IdX antibodies. Furthermore, spleen cells from pretreated mice do not inhibit the capacity of spleen cells from normal mice transferred to irradiated recipients to produce E109IdX in response to BL. This indicates that the suppression of IdX production in the anti-BL system is T independent and probably represents direct inhibition of precursors by anti-IdX.     

The molecular basis of granuloma formation in schistosomiasis. III. In vivo effects of a T cell-derived suppressor effector factor and IL-2 on granuloma formation

Granuloma formation in schistosomiasis is characterized by the formation of a large lesion in acutely infected animals which subsequently decreases in size as disease progresses into the chronic phase. These in vivo studies confirm and extend previous in vitro observations on the regulation of granulomatous hypersensitivity by a T cell-derived suppressor effector factor (TseF). TseF regulation of granuloma formation in vivo and DTH are shown to be both antigenically and genetically restricted. This suppression is accompanied by a suppression of the ability of cells derived from TseF recipients to function in an in vitro assay of granuloma formation. Antigenic recognition, defined by cellular proliferation in response to antigenic stimulation, is uneffected by TseF administration. Administration of IL-2 reduces TseF function in acutely infected mice and results in increased liver granuloma size. However, the ability of cells derived from these animals to form granulomas in vitro is uneffected. Cells obtained from chronically infected IL-2 recipients do not produce TseF in vitro and granuloma size is increased in these animals. Animals receiving both IL-2 and TseF continue to demonstrate decreased granuloma formation, indicating that IL-2 does not effect the ability of preformed TseF to function. These observations suggest that TseF modulates granuloma formation in vivo and may interact with IL-2 in a dynamic process which determines the intensity of the granulomatous response.     

Pulmonary granuloma formation in murine toxocariasis: transfer of granulomatous hypersensitivity using bronchoalveolar lavage cells

A major drawback to studying granuloma formation in murine toxocariasis is the ability of the second-stage larva of Toxocara canis to escape from a developing granuloma, migrate elsewhere, and initiate granuloma formation anew. In an attempt to circumvent this difficulty, 2 different T. canis-derived antigenic preparations were covalently attached to Sepharose 4B beads and embolized into the microvasculature of the lungs of CBA/J mice that had been infected 10 days previously with 25 T. canis ova. Both T. canis egg extract (TEE) and T. canis exoantigens (TEX) were able to elicit antigen-specific granulomas 6 days postembolization as determined by both histologic and morphologic criteria. Histologically, the eosinophil-rich granulomas forming around antigen-coated beads embolized into infected mice resembled the developing granuloma previously described forming around the second-stage larva. Attempts to transfer granulomatous reactivity in this model using either immune spleen cells or immune serum were unsuccessful. Successful transfer of granulomatous hypersensitivity was achieved using cells obtained by bronchoalveolar lavage of previously infected mice. The results suggest the feasibility of using this embolic model of granuloma formation in murine toxocariasis.     

Transfer of agammaglobulinemia in the chicken. II. Characterization of the target of suppression

The T-independent adoptive primary and secondary responses of FP chicken spleen cells to B. abortus (BA) were suppressed by simultaneously transferred histocompatible spleen cells from agammaglobulinemic (Aγ) chickens previously injected with bursa cells. The response of spleen cells transferred with BA 2 days prior to suppressor cells was partially inhibited. Highly significant suppression of both 19 S and 7 S antibody formation was seen during the second week after memory cell transfer. When suppressor cells and primed spleen cells were transferred together and challenged with BA 2 weeks later the secondary responses were more inhibited in recipients that showed persistently decreased serum IgM than in those showing recovery toward normal IgM levels. Transfer of histocompatible suppressor cells into surgically bursectomized (SBX). irradiated, 4-week-old SC and FP strain recipients caused reduction or complete disappearance of serum IgM and lowered IgG levels, which correlated well with a decrease in plasma cell numbers in spleen and trident. Many recipients of both strains, examined 1 to 2 weeks after transfer, completely lacked plasma cells from gut-associated lymphoid tissues and from spleen. When such animals had been sensitized to BA prior to transfer and were challenged after recovery from suppression, they showed good secondary responses. Experiments with serially transferred memory cells using suppressed intermediate hosts also indicated survival of such cells in the face of marked suppression of antibody synthesis. Bursa follicles that were not destroyed by irradiation did not show any effect of the suppressor cells, although plasma cells often disappeared from the interfollicular areas. Intact irradiated recipients showed a greater tendency toward recovery from suppression than did SBX recipients. Although Ig-bearing cells in spleen and peripheral blood of suppressed animals were significantly lower than in irradiated SBX controls, they never disappeared as completely as did plasma cells and serum IgM. The results suggest a direct effect of suppressor cells on antibody-forming cells with a less marked effect on their precursors.     

In vivo molecular analysis of lymphokines involved in the murine immune response during Schistosoma mansoni infection. II. Quantification of IL-4 mRNA, IFN-gamma mRNA, and IL-2 mRNA levels in the granulomatous livers, mesenteric lymph nodes, and spleens during the course of modulation.

Parasite egg-induced granulomas are the primary pathogenic lesions in murine schistosomiasis mansoni. This cell-mediated granulomatous response is specific for soluble egg Ag and appears to be mediated predominantly by CD4+ Th2 cells. As infection progresses from the acute to the chronic phase, the cell-mediated anti-soluble egg Ag responses attenuate in a process termed modulation. In this study the hypothesis that modulation is effected by a chronic phase increase in Th2-inhibiting Th1 cell activity was investigated. Northern blot quantification of mRNA specific for the Th2 lymphokine, IL-4, and the Th1 lymphokines, IFN-gamma and IL-2, in the spleens, mesenteric lymph nodes, and granulomatous livers of mice infected for various lengths of time over the course of modulation was performed. Also, the capacity of mitogen- and Ag-stimulated spleen cells to produce message for these lymphokines was compared. Peak tissue levels of both IL-4 mRNA and IFN-gamma mRNA were seen in acutely infected mice, and levels of both messages declined as infection became chronic. Stimulated spleen cells from acutely infected mice also produced higher levels of IL-4 and IFN-gamma mRNA than cells from chronically infected mice. IL-2 mRNA was never detected in any tissue sample but was detected in the stimulated spleen cells, again with acute phase levels higher than chronic phase levels. Hence, this study shows no evidence for increased Th1 cell activity during chronic infection and suggests that modulation may be effected by a generalized suppression of lymphokine synthesis.     

Modulation of granulomatous hypersensitivity. V. Participation of histamine receptor positive and negative lymphocytes in the granulomatous response of Schistosoma mansoni-infected mice

The possible role of histamine and histamine-receptored inflammatory cells in the granulomatous response of Schistosoma mansoni-infected mice was examined. Special staining revealed the presence of numerous mast cells, many partially degranulated within the liver granulomas. Treatment of infected mice with cimetidine (an H2 receptor antagonist) enhanced, and diphenyhydramine (an H1 receptor antagonist) decreased the granulomatous response. Fluorescein-labeled histamine-rabbit serum albumin conjugate (H-FRSA) and unlabeled conjugate (H-RSA)-coated culture plates were used to identify and isolate cells with histamine receptors. A large proportion of granuloma macrophages, lymphocytes, eosinophils, neutrophils, and splenic lymphocytes had histamine receptors. Elution of adherent cells from H-RSA-coated culture plates with H1 or H2 receptor antagonists suggested that receptors on granuloma cells were predominately H1 with some granuloma lymphocytes bearing H2-type receptors. Splenic lymphocytes from infected mice were functionally divided according to the presence or absence of histamine receptors on their cell surface. Receptor-negative lymphocytes appeared to mediate SEA-stimulated MIF production (TDH cells) and participated in the adoptive transfer of suppression of granulomas (TH cells). Whereas, TS cells appeared to have histamine receptors. Based on these data, it is inferred that lymphocytes that regulate lymphokine production (TS cells) within the granuloma may be triggered via their histamine receptors to exert suppressive activity.