Showing papers on "Immune system published in 1982"

Corticosteroid-mediated immunoregulation in man.

Abstract: Glucocorticoids have profound and complex effects on the human immune response. However, the precise mechanisms of the corticosteroid-induced immunoregulation in man have not been precisely defined. Intracytoplasmic corticosteroid-specific receptors appear to be an important common pathway for steroid-induced changes, but variations of receptor parameters do not account for the multifaceted effects on the immune system. Human circulating mononuclear cells redistribute out of the intravascular compartment following treatment with corticosteroids. Although certain components at this redistribution phenomenon have been well-characterized, the importance of this compartmental cellular shift with respect to the mechanisms of corticosteroid-induced immunoregulation are less well-defined. Recent observations that activated lymphocytes may be sensitive to the lytic effects of glucocorticoids suggest that under certain situations the elimination of selected subsets of cells may be a relevant mechanism of corticosteroid-mediated immunoregulation in man. Corticosteroid-mediated effects on monocyte function may be an important mechanism of drug-induced immunoregulation in monocyte-dependent responses. In some experimental conditions, corticosteroids inhibit Interleukin 1 production by monocytes. The immunoregulatory effects of corticosteroids on lymphocyte immune responses are complex. In vitro corticosteroids appear to selectively affect early immunoregulatory events as opposed to altering an established response. Multiple sites of steroid-induced modulations of human B cell responses have been defined.

Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells.

Abstract: When treated with lipopolysaccharide (LPS), cultured murine astrocytes released significant amounts of prostaglandin E, which caused an inhibition of the in vitro proliferative response of C3H/HeJ thymocytes to mitogen. In addition, an interleukin 1 (IL 1)-like factor secreted by LPS-treated glia cell cultures and by C6 glioma cells was detected. The characterization of the factor as an IL 1-like mediator is based on the findings that the factor 1) enhances the mitogen-induced thymocyte proliferation, 2) exhibits no interleukin 2 (IL 2) activity, but 3) augments IL 2 production by mitogen-stimulated thymocytes, and 4) has a m.w. between 13,500 and 18,000 when generated in serum-free conditions. These observations suggest that astrocytes may interact with the immune system by elaborating nonspecific factors that modulate lymphocyte proliferation. This property of astrocytes may be important in the generation of specific immune responses in the brain, which is considered to be an immunologically privileged organ as it is anatomically sequestered from the immune system.

Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production.

Abstract: Corticosteroids have profound effects on functions of the macrophage associated with antigen presentation to T cells. The drugs inhibited the expression of surface I-region-associated (Ia) antigens by peritoneal macrophages both in vitro and in vivo, reduced the production of IL 1, and inhibited antigen presentation for T cell proliferation by macrophages. The doses of hydrocortisone and prednisolone that inhibited by 50% Ia expression in cultured macrophages ranged around 2 to 5 x 10(-8) M. These results could explain one mechanism by which corticosteroids suppress the induction of immune responses.

Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.

Abstract: On the basis of preceding studies showing that tumor-induced, T cell-mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor-sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells.

Cytotoxic t cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients.

Abstract: We studied 58 recipients of bone-marrow transplants to evaluate immune responses to cytomegalovirus infection. Such infection developed in 43 patients; it was fatal in 12, nonfatal in 23, and present at death from other causes in eight. All patients had low or absent cytomegalovirus-specific cytotoxic lymphocyte activity before the onset of infection. Cytomegalovirus-specific cytotoxic responses developed in all survivors, whereas only two patients with fatal infection had even low-level cytomegalovirus-specific cytotoxic responses. Natural and antibody-dependent killer-cell activities were depressed both before and during infection in patients with fatal infections, but not in those who survived. The outcome of the infection did not correlate with the nature of the underlying disease, the type of transplant received, the pretransplantation cytomegalovirus-antibody status, or lymphocyte-proliferation responses to cytomegalovirus antigens or concanavalin A. The correlation between effective virus-specific cytotoxic response and recovery from infection indicates that these effector cells probably mediate recovery from cytomegalovirus infection.

Cyclophosphamide -facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced

Abstract: Although the passive transfer of T cell-mediated immunity to growth of a tumor implant is relatively easy to demonstrate, it has proven extremely difficult to demonstrate that passively transferred, tumor-sensitized T cells have any therapeutic effect against an established growing tumor (1). The most likely reason for the refractoriness of established immunogenic tumors to adoptive immunotherapy with tumor-sensitized T cells was supplied by previous publications from this laboratory (2, 3), which show that progressive growth of an immunogenic tumor evokes the generation in its host of a T cell-mediated mechanism of immunosuppression. The existence of this mechanism of immunosuppression was revealed in two ways: first, by showing that although passively transferred, tumor-sensitized T ceils failed to cause the regression of tumors growing in normal mice, they caused the complete and permanent regression of the same-sized tumors growing in mice that had been made T cell deficient by thymectomy and irradiation; and second, by demonstrating that failure of passively transferred, sensitized T cells to cause the regression of tumors in normal mice was associated with the presence in these mice of splenic T cells capable of inhibiting adoptive T cell-mediated regression of tumors growing in T cell-deficient mice. On the basis of this and other evidence, it was hypothesized (2, 3) that the progressive growth of an immunogenic tumor evokes the generation of a state of T cell-mediated concomitant immunity that undergoes T cell-mediated negative regulation before enough effector T cells are produced to destroy the tumor. It was further hypothesized (4) that any attempt to cause tumor regression by the passive transfer of tumor-sensitized T cells represents an attempt to superimpose an adoptive immune response on an already ongoing concomitant immune response that may be undergoing negative regulation, depending on the size of the tumor. If this line of reasoning is correct, it should follow that any treatment that prevents the generation of concomitant immunity and of the suppressor T cells that negatively regulate it, should facilitate the antitumor function of passively transferred, tumor-sensitized T cells. The purpose of this paper is to show that a cyclophosphamide-treated, tumorbearing recipient can substitute for a T cell-deficient, tumor-bearing recipient for demonstrating that an established tumor can be caused to completely regress by the * Supported by grant CA-16642 from the National Cancer Institute, grant IM-266 from the American Cancer Society, and grant RR-05705 from the Division of Research Resources, National Institutes of Health.

Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells

Abstract: This paper describes the effects of two lysosomotropic compounds, ammonia and chloroquine, on the interaction of mononuclear phagocytes with immune T cells. The uptake and ingestion of Listeria monocytogenes by macrophages were not affected by the drugs; however, the macrophage catabolism of 125I-labeled Listeria was reduced in a dose-dependent way. The macrophage presentation of Listeria to T cells, an I-region-dependent phenomenon, was also inhibited. The degree of inhibition of catabolism paralleled that of antigen presentation. The inhibition of antigen presentation took place if the macrophages were treated before and during Listeria uptake; minimal inhibition took place if the macrophages were treated 30 min after Listeria ingestion, at which time a significant amount of bacteria was already catabolized. Our previous studies had shown that the macrophage-associated antigen recognized by T cells became apparent 30-60 min after uptake of Listeria. We conclude that ammonia and chloroquine affected an intracellular handling step required for the expression of the immunogen relevant for T-cell recognition.

Prostaglandins modulate macrophage ia expression.

Abstract: Prostaglandins are important modulators of inflammation and of humoral and cellular immune responses1–8. In order to evaluate a possible mechanism for the regulation of immune responses we have studied the effects of prostaglandins on the expression of I-region-associated (Ia) antigens by macrophages. The expression of these glycoproteins is essential for macrophages to function as antigen-presenting cells during the induction of immune responses9. The synthesis and membrane expression of Ia, however, is not a constitutive property of the phagocyte10 but is under regulation and a positive regulation of this process is exhibited by activated T cells11. In contrast, a negative regulation is conspicuously found in the neonate where a product from a young replicating macrophage inhibits the expression of Ia by the mature macrophages12. We show here that prostaglandins of the E series (PGE) are potent inhibitors of the expression of Ia-antigens on macrophages and that thromboxane B2 (TXB2) antagonizes the effect of PGE.

Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon

Abstract: A previously undescribed species of human leukocyte, or alpha, interferon is present in the serum of many patients with systemic lupus erythematosus. It was shown to be alpha-interferon by neutralization with specific antiserums, affinity column chromatography, and antiviral activity on bovine cells. However, 23 of 30 interferon samples tested were inactivated by incubation at pH 2, a characteristic of human "immune," or gamma, interferon. Multiple samples of interferon from the same patient had similar biological properties, but samples from different patients were not all identical, suggesting that several variants of this species of human alpha-interferon may exist.

Regulation of the in vitro antibody response by neuroendocrine hormones

Abstract: Treatment of lymphocytes with inducers of interferon α (IFN-α) results in the production of corticotropin (ACTH) and endorphin-like activities. The pro-opiomelanocortin-derived hormones ACTH and α-, β-, and γ-endorphin and the structurally related hormones [Leu]- and [Met]enkephalin were therefore tested for their effects on the in vitro antibody response of mouse spleen cells. ACTH and α-endorphin were potent inhibitors (≥80% suppression) of the antibody response to the T-cell-dependent antigen sheep erythrocytes at a concentration of 0.5 μM. [Met]- and [Leu]enkephalin were moderate inhibitors (approximately 60% suppression) at 0.2-2 μM, and β- and γ-endorphin were minimal inhibitors (approximately 20% suppression) at 5-6 μM. At higher concentrations ACTH also inhibited the antibody response to the T-cell-independent antigen dinitrophenyl-Ficoll, suggesting that T-cell function was more sensitive to blockage by these hormones than was B-cell function. ACTH and IFN had similar suppression properties; thus, the hormone-like activities associated with IFN-α may play a role in IFN-induced immunosuppression. α-Endorphin immunosuppression was blocked by naloxone, which suggested that α-endorphin exerted its effects through binding to opiate-like receptors on the spleen cells. The failure of β-endorphin to suppress the immune response significantly was not due to its failure to bind to the opiate-like receptors because it blocked α-endorphin-induced suppression. Direct evidence for both opiate and ACTH receptors on the spleen cells was obtained in binding studies with labeled enkephalin and ACTH. Such studies revealed the presence of both high- and low-affinity receptors. The data show that neuroendocrine polypeptide hormones can regulate the immune response.

Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells.

Abstract: Interferons produce a variety of biological effects on cells. They induce resistance to virus proliferation, inhibit cell growth, modify cell structure and differentiation, stimulate some immune functions and inhibit others. However, the different interferon (IFN) species may vary in their mechanism of action and, hence, in their relative efficiency for inducing each of the effect. IFN-gamma (type II) appears to show stronger immunoregulatory and growth inhibitory effects than antiviral effects, but this conclusion has been challenged in other reports. The aim of the present work is to compare the action of IFN-gamma and other (type I) interferons on the induction of (2'-5') oligo(A) synthetase which is probably part of the antiviral response and the induction of the histocompatibility HLA-A,-B,-C antigens. We have shown previously that the induction of both proteins is regulated by interferons at the mRNA level, but show here that IFN-gamma from stimulated human lymphocytes and from monkey cells transfected by cloned human IFN-gamma cDNA induced the HLA-A,-B,-C and beta 2-microglobulin mRNAs or proteins at concentrations over 100 times lower than those needed to induce the (2'-5')oligo(A) synthetase and the antiviral state. This difference was not found with IFN-alpha and -beta (type I).

Human dendritic cells. Enrichment and characterization from peripheral blood.

Abstract: Previous studies demonstrated that lymphoid tissues of mice and rats contain small numbers (less than 1 percent of nucleated cells) of dendritic cells (DC) with special cytologic, surface, and functional properties. We show here that similar DC represent 0.1-0.5 percent of human peripheral blood mononuclear cells. DC can be enriched to 20-60 percent purity by a multistep procedure analogous to that used in mice. Adherent peripheral blood mononuclear cells are cultured overnight, and the released cells are depleted of monocytes and B cells by readherence to plastic, rosetting with erythrocytes coated with anti-human IgG, and centrifugation in dense albumin columns. Enriched DC have similar cytologic features to rodent DC by light and electron microscopy. DC express HLA, and HLA-DR and the leukocyte-common antigens. They lack phagocytic capacity, receptors for antibody-coated and neuraminidase-treated erythrocytes, surface and intracellular Ig, esterase, peroxidase, and azurophilic granules. DC do not react with several monoclonal antibodies directed to phagocytes (OKM 1, "mac-1," 63D3, and 61D3) and T cells (OKT 3, 6, 8). Unlike the mouse, human DC express complement receptors. When maintained in culture for 4 d, human DC did not give rise to either B cells or monocytes. Therefore, DC identified by cytologic criteria are distinct from other leukocytes. Enriched populations of DC have been compared to fractions enriched in monocytes, B cells, and T cells in three functional assays: stimulation of the primary allogeneic mixed leukocyte reaction, stimulation of the primary syngeneic MLR, and accessory function for the proliferation of periodate- modified T cells. In each case, the DC fraction was 10-fold or more active than other cell fractions. We conclude that DC circulate in man, and represent the principal cell type required for the initiation of several immune responses.

Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus erythematosus.

Abstract: This study reports quantitative information on the concentration of complement receptor for C3b and C4b (CR1) on erythrocytes from normal individuals and patients with immune complex disease. The measurements were performed by an immunoradiometric assay using monoclonal antibodies against CR1. The antibody specificity was confirmed by immunoprecipitation of CR1 from extracts of surface-labeled cells, by inhibition of rosette formation between B lymphocytes and the erythrocytes intermediate EAC14oxy23b, and by the characteristic distribution of the antigen among cells of human peripheral blood. The number of CR1 molecules in erythrocytes from 52 normal individuals was estimated as 1,410 +/- 620. No significant differences in CR1 levels were observed when individuals were grouped by sex, age, or blood groups. In patients with SLE and rheumatoid arthritis, the number of CR1 molecules per RBC was significantly lower, i.e., 600 +/- 307 and 903 +/- 417, respectively. CR1 levels were normal in asthmatics undergoing long-term treatment with prednisone. In SLE patients, significant correlations were found between CR1 levels, C4 hemolytic titers, and levels of circulating immune complexes. In two out of four patients with SLE, CR1 levels increased significantly during remission, showing that the deficiency is, at least in part, reversible. The deficiency in CR1 could be genetically controlled or could represent an epiphenomenon caused by the interaction of the receptor with a ligand present in the circulation of patients.

The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity.

Abstract: Publisher Summary Studies of the mouse strain have identified the gene, or closely linked group of genes, responsible for the immune defect, and it has been named “xid.” This chapter summarizes the known functional immune defects associated with xid and discusses the cellular basis for these defects. The X-chromosomes of mice and men influence the immunological function of these species in a number of interesting ways. In studies of the influence of the murine X-chromosome on serum IgM levels, it was shown that the mean values of serum IgM were higher in female mice than in males of two different mouse strains. However, in contrast to humans with Turner's syndrome (XO), who had lower mean serum IgM values than did normal XX females, the mean serum concentrations of IgM in XO mice were similar to that found in normal female mice. An X-linked form of severe combined immunodeficiency disease is described in the chapter. Children with this disease have variable degrees of lymphopenia, with small foci of lymphocytes in their lymph nodes and spleens. It is unclear if these patients have a primary B- or T-lymphocyte or stem cell defect. Spleens from either CBA/N or defective F1 male mice are considerably smaller than those of normal mice and the number of nucleated cells/spleen reflects this difference. The absence of thymus-independent type 2 (TI-2) responses in immune-defective mice and the apparent B-cell abnormality in this strain is related to an isolated dysfunction in otherwise normal B cells of these mice. It has been detected in studies that the xid defect could impair thymic-dependent (TD) responses by the induction of hapten-specific suppression without altering the development of memory B cells.

Decreased levels of helper T cells: a possible cause of immunodeficiency in pregnancy.

Abstract: DECREASED maternal immune responsiveness during pregnancy may partly explain the survival of the fetus as an allograft. It may also account for changes in disease activity and antibody production i...

Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2.

Abstract: Spleen cells from C57BL/6 mice immunized in vivo with a syngeneic Friend virus-induced leukemia, FBL-3, were specifically activated by culture for 7 d with FBL-3, then nonspecifically induced to proliferate in vitro for 12 d by addition of supernatants from concanavalin A-stimulated lymphocytes containing interleukin 2 (IL-2). Such long-term cultured T lymphocytes have previously been shown to specifically lyse FBL-3 and to mediate specific adoptive therapy of advanced disseminated FBL-3 when used as an adjunct to cyclophosphamide (CY) in adoptive chemoimmunotherapy. Because the cultured cells are dependent upon IL-2 for proliferation and survival in vitro, their efficacy in vivo is potentially limited by the availability of endogenous IL-2. Thus, the aim of the current study was to determine whether exogenously administered purified IL-2 could augment the in vivo efficacy of long-term cultured T lymphocytes. Purified IL-2 alone or as an adjunct to CY as ineffective in tumor therapy. However, IL-2 was extremely effective in augmenting the efficacy of IL-2-dependent long-term cultured T lymphocytes in adoptive chemoimmunotherapy. The mechanism by which IL-2 functions in vivo is presumably by promoting in vivo growth and/or survival of adoptively transferred cells. This assumption was supported by the findings that IL-2 did not enhance the modest therapeutic efficacy of irradiated long-term cultured cells that were incapable of proliferating in the host and was ineffective in augmenting the in vivo efficacy of noncultured immune cells that are not immediately dependent upon exogenous IL-2 for survival.

Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2

Abstract: We have studied the ability of immunized lymphoid cells expanded in IL-2 to mediate the cure of mice with localized and disseminated syngeneic lymphoma. Mice received 500 rad total-body irradiation before injection of tumor into the footpad. Mice were treated 5 d later when a palpable local tumor and disseminated metastases were present. Intravenous injection of in vivo immune lymphocytes cured 93% of all mice, significantly better than any control group (P less than 0.0005). Immune cells, secondarily sensitized to the FBL-3 tumor in vitro, also conferred significant survival benefit (P less than 0.005) when injected intravenously, curing 79% of the animals treated. When these in vitro sensitized cells were expanded in IL-2, 8-10-fold over 7 d, 93% of the animals thus treated were cured, (P less than 0.005). When these cells were grown for multiple generations in IL-2 they retained their ability to cure mice (56% cured, P less than 0.01). This is the first demonstration that intravenous injection of sensitized cells grown in long term culture in IL-2 is capable of curing mice of established local and disseminated syngeneic tumor.

Dissection of immunoregulatory subpopulations of T lymphocytes within the helper and suppressor sublineages in man.

Abstract: The helper/inducer (Leu-3) and suppressor/cytotoxic (Leu-2) sublineages of human peripheral blood T cells can both the subdivided into functionally distinct subsets with anti-Leu-8, a new monoclonal antibody that identifies 75 +/- 10% of the Leu-3 cells and 60 +/- 10% of the Leu-2 cells. Using the autologous MLR as a T cell-dependent stimulus for immunoglobulin synthesis, we have shown that the major helper effect for antibody formation lies within the numerically minor Leu-3,8- subset. In addition, neither Leu-2,8- cells alone suppress Leu-3-induced immunoglobulin synthesis, but in combination these subsets are markedly inhibitory. These results indicate that at least two phenotypically distinct cell types of suppressor lineage interact to produce suppression of an immune response in man.

Effect of cyclophosphamide on immunological control mechanisms.

Abstract: Cyclophosphamide (CY) given before immunization causes greatly increased delayed hypersensitivity skin reactions. Increased cell-mediated immunity is associated with depletion of B-lymphocytes from lymphoid tissue and a depression of those lymphocytes whose precursors turn over more rapidly. In the guinea pig, replacement studies showed that the depleted cells were not T-lymphocytes and had immunoglobulin adherent to their surface, a characteristic of B-lymphocytes. Delayed hypersensitivity reactions increased by CY include chemical contact sensitivity, the tuberculin reaction, delayed hypersensitivity to tularemia vaccine and the Jones-Mote reaction to soluble protein antigens. Pretreatment with CY can also increase the antibody response to some antigens, but depress the response to others. In addition, CY has been found to reverse immunological tolerance where this form of unresponsiveness is due to suppressor cells. CY can also enhance the immune response following depression by antigenic competition or desensitization. Other drugs with a similar, but lesser, effect include melphalan, azathioprine and methotrexate.

Expression of lyt-1 by a subset of b lymphocytes.

Abstract: Using two-color flow cytometry and multiparameter data analysis, we have shown that the IgM bright, large subset of mouse splenic B lymphocytes express Lyt-1. This is not due to B cell uptake of immune complexes of Lyt-1 and antibody from T cells. The IgM bright cells of autoimmune NZB mice express more Lyt-1 than normal controls. This is because IgM containing plasmablasts, which are greatly increased in NZB spleens, are Lyt-1+. NZB spleen also contains more cells that are Lyt-1+ (but perhaps Lyt-1.2-), Thy-1.2 dull, and smaller in size than cells in normal mice. Thus, Lyt-1 is common to the T and B cell precursor or is induced independently during the ontogeny of T and at least one subset of B cells. We suggest that it be called Lyt-1.

Human immune interferon

Abstract: Disclosed is a complete description of the preparation of novel, recombinant human immune interferon and des-CYS-TYR-CYS recombinant human immune interferon via recombinant DNA techniques utilizing any of an assortment of expression vectors and host cultures. The human immune (gamma) interferon (IFN-γ), is isolated and characterized in terms of DNA and amino acid sequences, physical attributes and biological activity.

Major histocompatibility antigens and mononuclear inflammatory infiltrate in benign nevomelanocytic proliferations and malignant melanoma.

Abstract: The presence of major histocompatibility antigens in malignant melanoma and benign nevomelanocytic lesions and the nature of associated mononuclear inflammatory cells were studied in situ by using monoclonal antibodies and an immunoperoxidase technique HLA-A,B,C (HLA) and beta 2-microglobulin (beta 2m) were found on malignant melanocytes in primary cutaneous and metastatic melanomas In contrast, HLA antigens were not identified on nevomelanocytes in benign hyperplasia or nevocellular nevi, although in some cases faint staining for beta 2m was present The staining of nevomelanocytes for HLA and beta 2 was variable in cases of nevomelanocytic dysplasia The degree of mononuclear cellular response correlated with the expression of HLA (or beta 2m) on nevomelanocytes Most of the inflammatory cells were identified as T cells The majority of T cells were of helper/inducer phenotype, whereas a lesser number were phenotypically suppressor/cytotoxic T cells The findings suggest that expression of HLA may be involved in triggering or eliciting a cellular immune response against dysplastic or malignant nevomelanocytes

Regulation of murine macrophage Ia antigen expression by an immune interferon-like lymphokine: inhibitory effect of endotoxin.

Abstract: The initiation of antigen-specific, T-dependent immune responses by macrophages requires their expression of Ia antigens. Ia antigen-deficient (Ia-) peritoneal exudate or P388D1 cell line macrophages, when incubated for 2 to 3 days with partially purified immune interferon (IFN-gamma), expressed Ia antigen, as detected by antibody-and-complement-mediated cytotoxicity. This paper reports that bacterial endotoxin (lipopolysaccharide, LPS) inhibited both IFN-gamma induction of macrophage Ia antigen expression and IFN maintenance of the Ia+ state in a dose-dependent manner. In the absence of IFN-gamma, LPS had no significant effect on macrophage Ia antigen expression. The inhibitory effects of LPS were abrogated by the addition of indomethacin into the culture medium. Further, 10(-10) to 10(-6) M exogenous prostaglandin E2 or 10(-6) to 10(-4) M exogenous dibutryl 3'5' cyclic adenosine monophosphate also inhibited IFN-gamma regulation of macrophage Ia antigen expression. The data suggest that LPS inhibits IFN-gamma regulation of macrophage Ia antigen expression by stimulating macrophage prostaglandin E2 production, and consequently enhancing intracellular cAMP levels. The data outline an inhibitory pathway involved in the regulation of macrophage Ia antigen expression, and may explain, in part, reported immunosuppressive effects of LPS.

Reconstitution after transplantation with T-lymphocyte-depleted HLA haplotype-mismatched bone marrow for severe combined immunodeficiency.

Abstract: Severe combined immunodeficiency (SCID) is potentially correctable by bone marrow transplantation if a patient has a suitable histocompatible donor. In the absence of an HLA-matched donor, lethal graft-versus-host disease (GVHD), which is mediated by alloreactive donor T cells, may occur. In an attempt to prevent GVHD in one SCID patient lacking a matched donor, we treated maternal haplomismatched bone marrow with a unique nonmitogenic T-cell-specific monoclonal antibody (anti-T12) and complement to remove mature T cells. Despite the removal of greater than 99% mature T cells, the child developed significant life-threatening GVHD, which was terminated by a 5-day course of intravenous anti-T12. Subsequently, immune reconstitution occurred by 6 wk: the mature circulating T cells proliferated in response to soluble and allo-antigens in vitro and provided help for B-cell immunoglobulin synthesis. The patient was removed from a protective environment and discharged without evidence of further infection. Both HLA and chromosomal analyses showed that the circulating cells in the patient were of maternal origin. More importantly, the maternal T cells were no longer reactive with recipient cells. Mixing experiments indicated that the state of tolerance that resulted in this chimera was not due to active suppression. We conclude that HLA-mismatched transplantation for SCID can be undertaken if mature alloreactive donor T lymphocytes are depleted before and after bone marrow grafting.