Showing papers on "Immune tolerance published in 1987"

Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response.

Abstract: Publisher Summary This chapter discusses the impact of new information concerning IgA physiology on the immune system. IgA should not be considered only as an isotype providing specific humoral protection of mucosal surfaces but as an integral component of the entire immune system. An unusual structural feature of human IgA is the heterogeneity of the molecular forms with characteristic distribution in various body fluids. Though most IgA in serum displays a typical four-polypeptide chain structure of the basic molecule with two Q and two light (L) chains, external secretions contain dimeric and tetrameric, disulfide-linked molecules associated with additional polypeptides-J (joining) chain and secretory component (SC). IgA-producing plasma cells are distributed in various lymphoid and nonlymphoid tissues and are particularly preponderant in the lamina propria of the gut; in salivary, lacrimal, and lactating mammary glands; and in the human bone marrow. IgA occurs in different body fluids in predominantly polymeric or monomeric (plasma, cerebrospinal fluid) forms with a characteristic distribution of IgAl and IgAz molecules. Under normal conditions, an absolute majority of IgA-containing cells in secretory glands and tissues also contain J chain whereas such cells in, for example, normal bone marrow does not. Staining with fluorochrome-labeled anti-J chain is enhanced by the pretreatment of alcohol-fixed tissue sections with acid urea, which leads to the exposure of masked antigenic determinants of intracellular J chain. Specialized lymphoid tissues associated with mucosal surfaces play an essential role in the induction and regulation of generalized immune responses in external secretions.

CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity.

Abstract: We have shown in a murine model system for acute, lethal cytomegalovirus (CMV) disease in the immunocompromised natural host that control of virus multiplication in tissues, protection from virus-caused tissue destruction, and survival are mediated by virus-specific CD8+ CD4-T lymphocytes. Protection from a lethal course of disease did not result in a rapid establishment of virus latency, but led to a long-lasting, persistent state of infection. The CD8- CD4+ subset of T lymphocytes was not effective by itself in controlling murine CMV (MCMV) multiplication in tissue or essential for the protective function of the CD8+ CD4- effector cells. The antiviral efficacy of the purified CD8+ CD4- subset was not impaired by preincubation with fibroblasts that presented viral structural antigens, but was significantly reduced after depletion of effector cells specific for the nonstructural immediate-early antigens of MCMV, which are specified by the first among a multitude of viral genes expressed during MCMV replication in permissive cells. Thus, MCMV disease provides the first example of a role for nonstructural herpesvirus immediate-early antigens in protective immunity.

Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones.

Abstract: Exposure of normal interleukin 2 (IL-2)-producing helper T-cell clones to antigen and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-treated antigen-presenting cells results in proliferative unresponsiveness to subsequent stimulation with antigen and normal antigen-presenting cells. In the present study, we have examined the molecular events that accompany the induction of this unresponsive state. T cells stimulated in this manner failed to produce IL-2, but interleukin 3, interferon-gamma, and IL-2 receptors were partially induced and T-cell receptor beta mRNA was fully induced. Although T-cell unresponsiveness correlated with an IL-2 production defect, addition of IL-2 during the induction phase failed to prevent development of the unresponsive state. The critical biochemical event appeared to be an increase in intracellular calcium. Removal of calcium from the medium prevented induction of the unresponsive state, whereas addition of the calcium ionophore ionomycin induced unresponsiveness as well as all of the related partial activation events. Thus, an increase in intracellular calcium under nonmitogenic conditions appears to initiate an alternative activation program that prevents the T cell from producing IL-2 in response to subsequent normal activation signals. The significance of this in vitro model for tolerance induction in vivo is discussed.

Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells.

Abstract: Transgenic mice expressing simian virus 40 T antigen under control of the insulin gene regulatory region vary in their response to this protein. Each lineage is characteristically either tolerant to T antigen, or not, in which case autoantibodies arise with high frequency, and lymphocytes infiltrate and disrupt the pancreatic islets. Both non-tolerance and the autoimmune response appear to result from delayed onset of T antigen expression during beta cell development.

Hematopoiesis and Suppressor Bone Marrow Cells in Mice Bearing Large Metastatic Lewis Lung Carcinoma Tumors

Abstract: Mice bearing a metastatic variant of Lewis lung carcinoma (LLC-C3) were studied to determine if there might be a relationship between tumor induced hematopoiesis and immune suppression. Growth of LLC-C3 in C57BL/6 mice corresponded with increased hematopoiesis and an increase in the proportion of monocytes in the peripheral blood, spleen, and bone marrow. The LLC-C3 cells secreted colony stimulating factor activity and, thus, could have directly stimulated the hematopoiesis in the hosts. As tumor growth progressed, the bone marrow of the tumor bearing mice became suppressive to T-cell blastogenesis. The bone marrow suppressor cells obtained from mice bearing large (greater than 3 g) LLC-C3 tumors were nonadherent to nylon wool, sensitive to treatment with L-leucine methyl ester, insensitive to treatment with anti-Thy-1.2 and complement, and mediated their suppression through an indomethacin sensitive mechanism. Secretion of colony stimulating factor activity by the LLC-C3 cells could have induced the appearance of the bone marrow suppressor cells since normal bone marrow cells which were cultured in the presence of LLC-C3 culture supernatants had an increased proportion of monocytes and were suppressive to T-lymphocyte blastogenesis. Our results suggest that the colony stimulating factor activity produced by LLC-C3 cells stimulates hematopoiesis which, in turn, could result in the appearance of bone marrow suppressor cells.

CD4 monoclonal antibody pairs for immunosuppression and tolerance induction

Abstract: A pair of rat anti-mouse CD4 monoclonal antibodies (mAb) have been selected which bind to different epitopes of the molecule. Both the mAb are rat IgG2b and show clear synergistic activity in complement lysis in vitro. When injected together in vivo, they exhibit an improved immunosuppressive effect, compared to each antibody alone, on allogeneic graft rejection, humoral responses and on tolerance induction. Limiting dilution analysis indicates that the in vivo depletion of interleukin 2-producing cells is improved using both mAb by 2-3-fold over that obtained with the individual antibodies. As little as 60 ng per mouse of the CD4 antibody pair was sufficient to allow the induction of tolerance to human gamma-globulin, even without elimination of the CD4+ cells. The results suggest that appropriate antibody pairs may be good candidates for effective immunosuppressive serotherapy in man.

Islet allograft survival after a single course of treatment of recipient with antibody to L3T4.

Abstract: Allografts of pancreatic islets of Langerhans were induced to survive for an indefinite period in diabetic mice if, at the time of engraftment, the mice received a single course of treatment with a monoclonal antibody directed against the L3T4 determinant, a nonpolymorphic cell surface glycoprotein present on the cell surface of the murine T helper-inducer lymphocyte subset This treatment allowed the survival of islets of Langerhans transplanted across a major histocompatibility barrier without additional immunosuppression The results demonstrate that the lymphocyte subset defined by the expression of the L3T4 molecules is central to the induction of allograft rejection and provides a model for tolerance induction for organ allograft transplantation

Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-vs-host disease.

Abstract: The inoculation of B6D2F1 mice with T lymphocytes from the C57BL/6 parental strain induces an "immunosuppressive" graft-vs-host reaction (B6 GVH), whereas inoculation of T cells from the other, DBA/2 parental strain induces an "immunostimulatory" GVH reaction and a lupus-like disease (DBA GVH). The present study compares cytotoxic T lymphocyte (CTL) function in the spleens of these GVH mice as well as differences in the donor inoculum that could account for these different types of GVH. We observed that the B6 GVH induces an immunodeficiency that encompasses CTL precursors (and possibly T helper cells) and results in suppressor cells that abrogate responses to both trinitrophenyl (TNP)-modified self and third party alloantigens. In contrast, the DBA GVH induces only a T helper cell immunodeficiency and results in suppressor cells selective for class II restricted L3T4+ T helper cells. Chimeric T cells were detected in both types of GVH. In the B6 GVH both L3T4+ and Lyt-2+ donor cells were observed, although Lyt-2+ cells predominated. In the DBA GVH, donor T cells were almost exclusively of the L3T4+ phenotype. The lack of appreciable donor Lyt-2+ cells in the DBA GVH can be explained by a defect in the DBA donor inoculum manifested by a naturally occurring two-fold reduction in Lyt-2+ cell numbers as well as a nine-fold reduction in CTL precursors with anti-F1 specificity. T cells in the DBA inoculum, therefore, are predominantly L3T4+. A similar defect induced in B6 donor cells by anti-Lyt2 antibody and complement not only converted the suppressive GVH to a stimulatory GVH, as measured by anti-DNA antibodies, but also resulted in a T cell immune deficiency characteristic of the DBA GVH, i.e., a selective loss of the TNP-self CTL response. Thus the presence or absence of adequate numbers of functioning Lyt-2+ cells in the donor inoculum is correlated with the development of either a suppressive or stimulatory GVH, respectively. That donor Lyt-2+ cells mediate a suppressive GVH through cytolytic mechanisms is evidenced by greater than 70% reduction in B6 GVH spleen cell numbers and readily demonstrable anti-F1 CTL activity by these spleen cells despite an inability to generate anti-allogeneic or anti-TNP self CTL activity even in the presence of added T helper factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance.

Abstract: Autoimmune diseases appeared frequently in adults in the prostate and stomach of C3.129 mice after thymectomy on day 3 (Tx-3) without any additional treatment. Lesions of both organs could be completely prevented by a single i.p. injection of spleen cells from syngeneic adult mouse on day 4. For prevention of prostatis, the most effective cell source was normal males (4 X 10(6); normal females or Orx-0 males were less effective as the cell source, and higher doses of cells (4 X 10(7)) were needed. In contrast, spleen cells (4 X 10(6)) from these three donors had equivalent capacity for the prevention of gastritis. Similar autoimmune prostatis developed at very high frequency when spleen cells (4 X 10(6)) from normal females or Orx-0 males, but not from normal males, were injected i.p. into C3.129 nu/nu mice at 4 d. However, no sign of prostatis was found in nu/+ recipients. Injection of a larger dose (4 X 10(7)) from the same donors was not effective for induction of prostatis. Gastritis could not be induced in nu/nu mice by this procedure. Injection of spleen cells from Tx-3 males or females was effective for induction of both prostatis and gastritis in nu/nu recipients. It was also shown that a T cell population (Thy-1.2+, Ig-) had the capacity to prevent and to induce autoimmune diseases. These results together strongly suggest a role for active tissue-specific suppressor T cells in self tolerance, and elimination of such T cell populations causes autoimmunity.

Experimental cutaneous leishmaniasis. II. A possible role for prostaglandins in exacerbation of disease in Leishmania major-infected BALB/c mice.

Abstract: Leishmania major infection in genetically susceptible BALB/c mice is associated with the development of chronic primary lesions as well as multiple metastatic lesions. Spleen cells from these mice were shown to have depressed in vitro responses to concanavalin A (Con A) that coincided with the development of indomethacin-sensitive suppressor cells. Depressed responses to Con A were noted as early as 1 wk after parasite inoculation and correlated with the increased production of prostaglandin E2 (PGE2) by spleen cells from infected mice. Mice induced by prior irradiation (550 rad) to heal infection did not develop indomethacin-reversible depression in responsiveness to Con A. Although macrophages appear to be the major source of PGE2 production, in vitro studies indicate that infection per se is not a sufficient stimulus to initiate prostaglandin (PG) synthesis, suggesting the involvement of other cell types. Mice treated in vivo with indomethacin exhibited significantly fewer metastatic lesions than control mice, suggesting that PG may play a role in the exacerbation of cutaneous disease in these animals.

Persistence of oral tolerance in mice fed ovalbumin is different for humoral and cell-mediated immune responses.

Abstract: The duration of oral tolerance after a single feed of OVA at the age of 6 weeks was studied in BDF1 mice. Significant suppression of systemic antibody responses was present 3 months later, but not at 6.5 months; in contrast, at all times studied from 2 weeks to 17 months after an OVA feed there was suppression of systemic CMI to OVA as measured by an in vivo skin test. This indicates that the two limbs of the immune response differ in the factors responsible for the maintenance of oral tolerance.

Contrasuppression in autoimmunity. Abnormal contrasuppression facilitates expression of nephritogenic effector T cells and interstitial nephritis in kdkd mice.

Abstract: We have used the murine model of spontaneous autoimmune interstitial nephritis in kdkd mice to examine the importance of abnormal immunoregulation in the expression of disease. T cells from naive congenic CBA/Ca mice suppress both histologic renal injury in the kdkd strain as well as the DTH reactivity to CBA/Ca renal tubular antigens mediated by lymphocytes from nephritic kdkd mice. These antigen-specific suppressor T cells are Lyt-2+, L3T4+, I-Jk+, genetically dominant and I-Jk restricted. Unfractionated spleen cells from young, prenephritic kdkd mice also demonstrate such suppressor function. Shortly preceding disease onset, however, net suppression is functionally bypassed by emergent contrasuppressor T cells. These regulatory cells are also Lyt-2+ and I-Jk+, and adhere both to the Vicia Villosa lectin and CBA/Ca TBM. By admixing these contrasuppressor cells with spleen cells from non-disease-prone CBA/Ca mice we were able to demonstrate the presence of DTH-reactive and nephritogenic effector cells in the latter population. Such nephritogenic effector cells could also be simply demonstrated after depletion of the suppressor cells with anti-I-Jk mAbs and complement. These findings support a role for contrasuppressor cells in the abrogation of tolerance to parenchymal self-antigens.

Alloantigen persistence in induction and maintenance of transplantation tolerance.

Abstract: Infusion of parental bone marrow cells into F1 hybrids conditioned by total lymphoid irradiation (TLI) results in chimeras with a high percentage of donor-type cells, and without clinical signs of graft-vs.-host reaction. In these chimeras, a state of tolerance has been shown to be associated with paucity of cytotoxic T lymphocyte percursors (pCTL) reactive with host-type alloantigens. To determine whether the presence of tolerizing alloantigens is essential for maintenance of unresponsiveness, lymphohematopoietic cells obtained from such tolerant chimeras were transferred into supralethally irradiated recipients of two different genotypes: in one case the adoptive recipients were syngeneic with host-type cells, and in the other they were syngeneic with donor-type cells of the original chimeras, thus providing the chimeric cells with a tolerogen-free environment. After "parking" for 4 d in syngeneic donor-type mice, the transferred cells displayed a marked increase in the frequency of pCTL directed against tolerizing alloantigens, whereas a low pCTL frequency directed against the same H-2 target cells was maintained in allogeneic tolerizing-type adoptive recipients. Multiple injections of adoptive donor-type mice with tolerizing-type cells of the original chimera reestablished a low level of cytotoxic precursors. Cytotoxic activity against unrelated alloantigens was independent of the presence of tolerogen-presenting cells in the adoptively transferred mice. Our experimental model suggests that persistence of cells bearing tolerizing alloantigens is an essential requirement for maintenance of previously established tolerance.

Immunity to herpes simplex virus type 2. Suppression of virus-induced immune responses in ultraviolet B-irradiated mice.

Abstract: Ultraviolet B irradiation (280 to 320 nm) of mice at the site of intradermal infection with herpes simplex virus type 2 increased the severity of the herpes simplex virus type 2 disease and decreased delayed-type hypersensitivity (DTH) responses to viral antigen Decrease in DTH resulted from the induction of suppressor T cells, as evidenced by the ability of spleen cells from UV-irradiated mice to inhibit DTH and proliferative responses after adoptive transfer Lymph node cells from UV-irradiated animals did not transfer suppression DTH was suppressed at the induction but not the expression phase Suppressor T cells were Lyt-1+, L3T4+, and their activity was antigen-specific However, after in vitro culture of spleen cells from UV-irradiated mice with herpes simplex virus type 2 antigen, suppressor activity was mediated by Lyt-2+ cells Culture supernatants contained soluble nonantigen-specific suppressive factors

Cell-mediated immune tolerance to HSV-1 antigens associated with reduced susceptibility to HSV-1 corneal lesions.

Abstract: We have investigated the involvement of cell-mediated immune responses to Herpes simplex virus type 1 (HSV-1) in the pathogenesis of HSV-1 induced corneal stromal lesions in mice. Topical corneal (TC) HSV-1 infection induced a vigorous delayed hypersensitivity response, as well as lymphoproliferative and cytotoxic responses in the regional lymph nodes. The cytotoxic response involved HSV-1 specific and genetically restricted cytotoxic T lymphocytes, and activated natural killer cells. Half of the TC HSV-1 infected mice developed corneal stromal inflammation and scarring, the cause of visual morbidity in human herpetic disease. However, injection of HSV-1 into the ocular anterior chamber (AC) prior to, or simultaneously with, TC HSV-1 infection resulted in a profound state of cell-mediated immune tolerance of HSV-1 antigens. The tolerance was characterized by a substantial reduction in delayed hypersensitivity, lymphoproliferative, and cytotoxic responses to HSV-1 and was associated with virtually complete protection from corneal stromal lesions induced by HSV-1. These findings suggest a pathogenetic role for cell-mediated immunity and indicate the feasibility of preventing stromal disease through proper manipulation of the immune response.

Simian virus 40 (SV40)-transgenic mice that develop tumors are specifically tolerant to SV40 T antigen.

Abstract: The ability to mount an immune response to simian virus 40 (SV40) T antigen was evaluated using mice from two distinct SV40 transgenic lines derived from injection of the same gene construct. Our studies demonstrate functional immune tolerance to SV40 T antigen in a SV40 transgenic line that consistently develops tumors of the choroid plexus by 7 mo of age. Antibodies to SV40 T antigen are undetectable in the serum of these animals; furthermore, mice from this line are unable to generate SV40-specific CTL after primary or secondary immunization with the virus, although they mount a normal CTL response to vaccinia virus when appropriately immunized. In contrast, we find that mice from a second transgenic line of low tumor incidence can mount a humoral response to SV40 T antigen, and upon immunization they generally respond with a vigorous cytotoxic T cell response to SV40 T antigen. These data suggest that specific immune tolerance to the product of an integrated viral oncogene may be induced, and is likely a reflection of the time in development at which the gene product first appears. Immune tolerance or responsiveness to the endogenous oncogene product may in turn play a role in the tumorigenic potential of such genes.

Tolerance induction in mice by conjugates of monoclonal immunoglobulins and monomethoxypolyethylene glycol. Transfer of tolerance by T cells and by T cell extracts.

Abstract: The specific tolerance induced in mice by conjugates of human monoclonal IgG (HIgG) with monomethoxypolyethylene glycol (mPEG) was transferred to normal mice by spleen cells or a surface immunoglobulin negative (sIg-) Lyt-2+ subpopulation of these cells. Although transferable tolerance was demonstrable 6 to 14 days after treatment of the cell donors with tolerogen, the state of tolerance persisted in the treated mice for at least 43 days. Moreover, an extract prepared by freezing and thawing of the sIg- spleen cells obtained from mice 6 days after treatment with HIgG(mPEG)20 was capable of reducing (greater than 85%) the immune response of normal mice to heat aggregated HIgG. On the basis of these results, it is suggested that similar tolerogenic mPEG derivatives of xenogeneic monoclonal immunoglobulins (XIg) may prove to be useful therapeutic agents in man when administered before treatment with the unmodified XIg.

Lack of immune deficiency in sarcoidosis: compartmentalisation of the immune response.

Abstract: The original findings of peripheral anergy in sarcoidosis led to the conclusion that sarcoidosis was a disease associated with immune deficiency, but patients with sarcoidosis do not appear to suffer from repeated infections suggestive of immune suppression. With the technique of bronchoalveolar lavage it is now possible to examine the local immune response within the lung, the most commonly affected organ in sarcoidosis. In this study three different indices of cell mediated immunity (lymphocyte transformation, interleukin-2 production, and interleukin-1 production) have been examined by comparison of cells recovered by lavage with those collected from peripheral blood. It was found that in vitro anergy was confined to peripheral blood cells, where all three markers of the immune response used in this study was impaired in the 12 patients with sarcoidosis group when compared with results in the 12 controls, with the most depressed responses seen in those patients classified as having active disease (lymphocyte proliferation 45% (SD 17%); interleukin-2 production 44% (13%), and interleukin-1 production 31% (10%) of control levels). By contrast, T lymphocytes recovered from the lungs of patients with sarcoidosis showed a greater response than did those from controls in terms of lymphocyte transformation and interleukin-2 production; these differences were greatest in those with active disease (lymphocyte proliferation 209% (27%) and interleukin-2 production 202% (19%) of control levels). Interleukin-1 production by cells of the monocyte lineage recovered from the lung gave similar results to those of the control and sarcoid groups. It is concluded that the anergy seen in the peripheral blood compartment possibly reflects redistribution of T lymphocytes rather than a generalised immune deficiency.

The bovine autologous Theileria mixed leucocyte reaction: influence of monocytes and phenotype of the parasitized stimulator cell on proliferation and parasite specificity.

Abstract: In the autologous Theileria mixed leucocyte reaction (MLR), irradiated Theileria parva-infected cells induce proliferative responses in autologous peripheral blood mononuclear leucocytes (PBM), irrespective of the immune status of the donor animal. In this paper we have analysed the cellular basis of this response in naive and immune cattle to determine the Theileria specificity of the response. The magnitude of proliferation is dependent on two parameters, namely the presence or absence of monocytes in the responder population, and the phenotype of the parasitized stimulator cells, both of which appeared to be independent of the immune status of the donor animal. Monocyte-depleted responders invariably gave stronger proliferative responses but generated cytotoxicity from immune cattle that tended to be less genetically restricted. Marked differences were observed in the stimulatory capacity of cloned parasitized T-cell and non-T cell lines. At least part of this variation was associated with differences in the capacity of the parasitized cells to secrete soluble suppressive factors and possibly also stimulatory factors. Two observations indicated that, in immune cattle, part of the proliferative response in the autologous Theileria MLR is parasite-specific. First, stimulator cells fixed with glutaraldehyde stimulated proliferative responses in monocyte depleted PBM from immune animals but not naive animals. Second, in autologous Theileria MLRs with intact PBM, genetically restricted cytotoxic cells were generated from immune but not naive animals. While monocytes seem not to be required for induction of the parasite-specific component of the response, their absence from the assay when viable stimulator cells are utilized appears to enhance the non-specific component of the proliferative and cytotoxic responses.

Role of T cell-derived lymphokines in two models of B-cell tolerance.

Abstract: Engagement of surface immutioglobulin (slg) receptors by antigen initiates a series of biochemical signals that affect B-cell growth and differentiation. When this interaction occurs with immature (e.g. neonatal) B cells, a state of unresponsiveness or tolerance usually results. In contrast, mature B cells can be activated (i.e. positively signalled to proliferate/difTerentiate) by crosslinking of their slg receptors by antigen or anti-Ig antibodies. However, mature B cells also can be rendered unresponsive by concomitant interaction of anti-Ig/tolerogen with Fc receptors (Klaus et al. 1987, Waldschmidt & Vitetta 1985, Warner and Scott, unpublished). Several model systems employing polyclonal populations of normal B cells have been used to examine the molecular pathways of positive signalling via slg (Moller 1987). Over the past decade, our laboratory has been examining the biochemical events associated with both positive and negative signalling in relatively homogeneous populations of antigen-specific B cells (Scott et al. 1980, Pillai et al. 1984). These studies have allowed us to compare hapten-specific cells derived from normal, primed or tolerant individuals in terms of their ability to be stimulated by a variety of known B-cell activators (antigen, anti-Ig, mitogen, T-cell factors) as measured by increase in cell size, hyper-Ia expression, entry in the S phase of the cell cycle, and the appearance of antibody-secreting cells. The low frequency of antigen-specific B cells, and thus the difficulty in obtaining large numbers of cells, has severely limited our ability to examine early

Induction of a macrophage-suppressive lymphokine by soluble cryptococcal antigens and its association with models of immunologic tolerance.

Abstract: Soluble extracts of Cryptococcus neoformans were examined for their ability to induce a macrophage-regulatory T-suppressor cell known to appear in the spleens of mice infected with cryptococci. Suppressor cells were induced by injection of extracts of encapsulated or thinly encapsulated strains of cryptococci. Dose-response analysis showed that as little as 25 micrograms of soluble capsular polysaccharide antigen could induce significant suppressor cell activity, with maximum suppression occurring at a dose of 100 micrograms. The suppressor cells appeared within 1 week of injection of antigen and persisted for at least 2 months. Suppressor cells were induced in animals given tolerogenic doses of levan, human gamma globulin, and soluble capsular polysaccharide antigen. When these same antigens were administered in immunogenic form, no suppressor cell activity was detected. Therefore, the suppressive mechanism was common to models of immunologic tolerance and was not unique to cryptococcal disease or cryptococcal capsular polysaccharide antigen. The phagocytosis-inhibiting lymphokine produced by the suppressor cell population completely inhibited the phagocytic activity of only a portion of peritoneal exudate cells. Other macrophages in the population were not totally inhibited but exhibited a reduction in the number of yeast cells engulfed.

A genetically determined lack of oral tolerance to ovalbumin is due to failure of the immune system to respond to intestinally derived tolerogen.

Abstract: In this study we have examined whether differences between mouse strains in the induction of tolerance after feeding ovalbumin (OVA) are due to differences in intestinal processing of OVA or are determined by the systemic immune system. Compared with major histocompatibility complex (MHC)-congenic BALB/c mice, BALB/B mice develop much less tolerance of systemic delayed-type hypersensitivity (DTH) and humoral immunity after feeding OVA and this defect is also expressed partially in (BALB/B × BALB/c)F1 animals. Serum taken from either BALB/c or BALB/B mice fed OVA 1 h before produced significant suppression of systemic DTH responses in BALB/c, but not in BALB/B mice. Although OVA-fed BALB/B serum was slightly less tolerogenic than BALB/c serum, we conclude that the defective induction of oral tolerance in BALB/B mice is due primarily to a MHC-influenced defect with the immune system. These findings support the idea that clinical food-sensitive enteropathy reflects an immune response gene-controlled defect in tolerance to dietary proteins.

Modulation of the induction and circumvention of immunological tolerance to human gamma-globulin by interleukin 1.

Abstract: As with agents capable of causing the release of IL 1, IL 1 itself is capable of modulating certain tolerance-inducing events. Under the condition used in the present study, it previously has been firmly established that injection of A/J mice with DHGG induces a state of antigen-specific tolerance in both T helper (Th) and B cells. The tolerance in the B cell is of long duration, whereas that in the B cell is of shorter duration. Recombinant IL 1 (rIL 1) given shortly after the tolerogen DHGG results in the inhibition of the induction of tolerance resulting in antibody production. The induction of tolerance is inhibited at both its antigen-specific Th cell and B cell levels, although the latter may be caused by the former. The inhibition of the induction of tolerance by rIL 1 is not correlated to the generation of antigen-specific T suppressor cells. IL 1 mimics lipopolysaccharide and 8-bromoguanosine, which generate IL 1 production, in its ability to interfere with the in vivo induction of tolerance. However, in contrast to these latter mitogens which cause both terminal differentiation of B cells and IL 1 production, IL 1 itself does not cause in vivo circumvention of long-term tolerant Th cells in the presence of competent B cells and antigen. These latter findings suggest that a signal(s) in addition to those delivered by IL 1 is required for activation of the B cell compartment recovering from tolerance to antibody production. AHGG (immunogen) is a potent generator of IL 1 release, whereas DHGG has no effect on IL 1 release from macrophages and AHGG inhibits the induction of tolerance by DHGG. These latter results suggest that the lack of an IL 1 signal may be responsible for the deliverance of a tolerogenic rather than an immunogenic signal to the Th cell.

Drug-induced tolerance to allografts in mice. XII. The relationships between tolerance, chimerism, and graft-versus-host disease.

Abstract: When AKR/J Sea (AKR, H-2k) mice were primed i.v. with 1 X 10(8) viable spleen cells from naive C3H/He Slc (C3H, H-2k) mice and treated i.p. with 200 mg/kg cyclophosphamide (CP) 2 days later, a minimal degree of mixed chimerism associated with tolerance to C3H skin was established without graft-versus-host disease (GVHD) and maintained for at least one month. When AKR mice were primed i.v. with 1 X 10(8) viable spleen cells from C3H mice preimmunized i.v. 7 days earlier with 5 X 10(7) viable AKR spleen cells, and treated with 200 mg/kg CP, chimerism became exclusive, but lethal GVHD occurred in the AKR mice. Moreover, most of normal AKR mice primed with the preimmunized C3H spleen cells without CP died of GVHD. In contrast, in a major histocompatibility complex (MHC)-incompatible combination of AKR (H-2k)-C57BL/6 Cr Slc (B6, H-2b), mixed chimerism, tolerance to skin allografts, and GVHD were not observed, whether or not the mice had been treated with naive or preimmunized B6 spleen cells with or without CP.