Showing papers on "Immune system published in 1988"

Interleukin-2: inception, impact, and implications.

Abstract: Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.

Biology of interleukin 1.

Abstract: Interleukin 1 (IL 1) is a polypeptide that is produced after infection, injury, or antigenic challenge. Although the macrophage is a primary source of IL 1, epidermal, epithelial, lymphoid, and vascular tissues synthesize IL 1. When IL 1 gains access to the circulation, it acts like a hormone and induces a broad spectrum of systemic changes in neurological, metabolic, hematologic, and endocrinologic systems. Some of the IL 1 that is synthesized remains associated with the plasma membrane and induces changes in local tissues without producing systemic responses. IL 1 affects mesenchymal tissue remodeling where it contributes to both destructive and repair processes. IL 1 activates lymphocytes and plays an important role in the initiation of the immune response. Receptors for IL 1 have been identified, but receptors are scarce and their affinities often do not match the potency of the biological response. The most consistent property of IL 1 is up-regulation of cellular metabolism and increased expression of several genes coding for biologically active molecules. IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites. IL 1 also acts synergistically with other cytokines, particularly tumor necrosis factor. The multitude of biological responses to IL 1 is an example of the rapid adaptive changes that take place to increase the host's defensive mechanisms.

The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.

Abstract: The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.

Transfer of a functional human immune system to mice with severe combined immunodeficiency

Abstract: The pressing need for a better experimental system for AIDS research has brought into sharp focus the shortcomings of available animal models and the practical and ethical limitations of studies of immune responses and viral pathogenesis in humans. Current studies of the human immune responses are limited to relatively restrictive in vivo experiments and several in vitro systems that, although useful, allow only short-term studies and support responses to a few antigens. Neither model is particularly amenable to studies of the pathogenesis of diseases of the immune system. We report here that injection of human peripheral blood leukocytes (PBL) can result in the stable long-term reconstitution of a functional human immune system in mice with severe combined immunodeficiency (SCID). Human PBL transplanted to SCID mice increase in number and survive for at least six months; reconstituted mice show spontaneous secretion of human immunoglobulin and a specific human antibody response is induced following immunization with tetanus toxoid. All of the major cell populations present in PBL are found in the lymphoid tissue and blood of SCID recipients, although the relative proportions of B cells, T-cell subsets and monocytes/macrophages in long-term recipients differ from those found in normal PBL and, in mice transplanted with 50 x 10(6) or more PBL from Epstein-Barr virus (EBV)-seropositive donors, EBV-positive B-cell lymphomas often develop. Our results suggest that xenogeneic transplantation of human lymphoid cells into SCID mice may provide a useful model for the study of normal human immune function, the response of the immune system to pathogenic agents and early events in lymphomagensis.

Effect of neuropeptides on production of inflammatory cytokines by human monocytes

Abstract: Two groups of mediators, the neuropeptides substance P and K and the monocyte-derived cytokines, interact in the neural regulation of immunological and inflammatory responses. Substance P, substance K, and the carboxyl-terminal peptide SP(4-11) induce the release of interleukin-1, tumor necrosis factor-alpha, and interleukin-6 from human blood monocytes. The neuropeptide effects occur at low doses, are specific as shown by inhibition studies with a substance P antagonist, and require de novo protein synthesis. Since monocyte-derived cytokines regulate multiple cellular functions in inflammation and immunity and since neuropeptides can be released from peripheral nerve endings into surrounding tissues, these findings identify a potent mechanism for nervous system regulation of host defense responses.

Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones.

Abstract: A biphasic dose-response curve was observed when the IL-1-dependent HTL clone D10 was exposed to IL-1 plus supernatants from some activated T cell clones but not others. The active component that inhibited proliferation at high concentrations of these supernatants appeared to be IFN-gamma based on the following findings: 1) the biphasic pattern of responsiveness correlated with the presence of IFN-gamma in the supernatants; 2) an anti-IFN-gamma mAb augmented the proliferation of D10 cells to these supernatants; 3) rIFN-gamma inhibited profoundly the response of D10 cells stimulated with rIL-1 plus supernatant from activated D10 cells or with rIL-1 plus rIL-4; 4) the response of D10 cells to rIL-1 plus rIL-2 also was inhibited by rIFN-gamma, although to a lesser extent. The proliferation of an additional Th2 clone stimulated with rIL-1 plus rIL-4 or rIL-2 also was inhibited by rIFN-gamma, implicating IFN-gamma as an inhibitory lymphokine for Th2 cells in general. rIFN-gamma did not affect the proliferation of two Th1 clones, nor did it affect the proliferation of an unconventional HTL clone which produces both IL-4 and IFN-gamma and proliferates in response to IL-2 or IL-4 in an IL-1-independent fashion. The proliferation of D10 cells stimulated by Ag or by immobilized anti-CD3 antibody also was blocked by rIFN-gamma, whereas IL-4 production in response to these stimuli was unaffected, indicating that proliferation and not general cell function was specifically inhibited. Collectively, these data implicate IFN-gamma as a suppressive factor for the proliferation of the subset of HTL designated Th2, and suggest that the relative amounts of the various lymphokines present during an immune response may direct which T cell types increase in number.

IFN-gamma regulates the isotypes of Ig secreted during in vivo humoral immune responses.

Abstract: The lymphokine IFN-gamma has been shown in vitro to stimulate IgG2a secretion and inhibit IgG1 and IgE secretion by LPS-activated B lymphocytes. To determine whether IFN-gamma has a similar isotype regulatory role in vivo, we studied the abilities of rIFN-gamma and a mAb to IFN-gamma to modify the isotypes of Ig secreted in mice injected with a goat antibody to mouse IgD, which by itself induces large increases in levels of serum IgG1 and IgE and a relatively small increase in serum IgG2a. Multiple injections of IFN-gamma substantially inhibited production of IgG1 and IgE, and stimulated production of IgG2a in affinity purified goat antibody specific for mouse IgD-treated mice; anti-IFN-gamma antibody blocked the effects of IFN-gamma and in fact enhanced IgG1 and IgE secretion and inhibited the IgG2a response in these mice. The role of IFN-gamma in the selection of isotypes of Ig produced in response to injection of mice with the bacterium Brucella abortus (BA) was also studied, because killed, fixed BA are known to stimulate IFN secretion and a predominantly IgG2a antibody response. Anti-IFN-gamma antibody strongly suppressed IgG2a secretion and stimulated IgG1, but not IgE, secretion in BA-immunized mice. BA suppressed IgG1 and IgE secretion and enhanced IgG2a secretion in affinity purified goat antibody specific for mouse IgD-injected mice; treatment of these mice with anti-IFN-gamma antibody reversed the effects of BA on IgG1 and IgG2a secretion, but not the suppressive effect of BA on IgE secretion. These observations demonstrate that IFN-gamma has an important and perhaps unique physiologic role in the stimulation of IgG2a secretion and in the suppression of secretion of IgG1, whereas bacterial antigens can suppress IgE secretion by other mechanisms in addition to IFN-gamma secretion.

Current concepts: immunology. Monocytes and macrophages.

Abstract: MACROPHAGES play a central and essential part in the immune response by presenting antigen to lymphocytes during the development of specific immunity and by serving as supportive, "accessory" cells...

Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide.

Abstract: The clinical manifestations of AIDS (acquired immune deficiency syndrome) often include neuropsychiatric and neurological deficits1–4, including early memory loss and progressive dementia. HIV (human immunodeficiency virus), the aetiological agent of AIDS, is probably carried by infected macrophages in the central nervous system5–7. The virus enters cells by binding its envelope glycoprotein gp120 to the CD4 antigen8–10 present on brain and immune cells11–13. From the data reported in this paper, we now suggest that the neuronal deficits associated with HIV may not be entirely a result of infectivity, but that gp120 shed from HIV14–16 could directly produce the neuropathology as a result of its interference with endogenous neurotrophic substances. It is known that an analogue of a sequence contained in vasoactive intestinal peptide (VIP) occurs in all known sequenced gp120 isolates17–20 and that VIP is important for neuronal survival in cell culture21–23. Here we show that purified gp120 from two diverse HIV isolates and a recombinant gp120 from a third isolate were all potent in specifically producing significant neuronal cell death in dissociated hippocampal cultures derived from fetal mice, and that this could be reduced by monoclonal antibodies against the murine24 CD4 antigen and completely antagonized by VIP.

Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells.

Abstract: Freshly isolated, murine epidermal Langerhans cells (LC) are weak accessory cells for primary T cell-dependent immune responses, but increase their stimulatory capacity at least 20-fold progressively over a 3-d culture with keratinocytes We have studied the mediators of LC maturation LC enriched from 12-h epidermal cultures by negative selection do not survive when cultured for 60 h in standard medium LC survive and show increased stimulatory capacity for oxidative mitogenesis and the primary MLR when 30% keratinocyte-conditioned medium is included Of the three cytokines that are known to be produced by keratinocytes, only granulocyte/macrophage CSF (GM-CSF) maintains viability and increases stimulatory capacity IL-1 alone does not keep LC alive, but further enhances the stimulatory activity when combined with GM-CSF IL-3 has no effect The increase in LC stimulatory capacity is not due to increased Ia antigen expression, which does not change between 12 and 60 h Function is not simply due to improved viability, as GM-CSF does not enhance the function of 12-h LC when added to the short-term oxidative mitogenesis assay By generating LC with strong stimulating activity for resting T cells, GM-CSF and IL-1 may be critical in the sensitization phase of T cell-mediated immunity

Molecular Regulation of B Lymphocyte Response

Abstract: Antibodies are one of the key elements in the immune system. On the one hand, they play an essential role in protection against viral and bacterial infections; on the other hand, they are involved in certain autoimmune diseases and in immediate-type hypersensivity. B cells are the only euka­ ryotic cells that can produce antibody molecules. The regulated production of antibody molecules is one of the most complex examples of eukaryotic cell differentiation and one of those most. amenable to scientific in­ vestigation. Since the discovery of T and B cell interaction in the antibody response, the mechanism of the regulatory function(s) ofT cells in the B cell response has been one of the central issues in immunology. The existence ofT cell­ derived helper factors that promote B cell proliferation and antibody secretion was recognized in the early and mid 1970s. Dutton and his colleagues (1) as well as Schimpl & Wecker (2) demonstrated that culture supernatants of murine T cells stimulated by mixed lymphocyte reaction or by T cell mitogens could reconstitute the antibody response of T cell­ depleted splenic lymphocytes. Kishimoto and his colleagues (3) showed that anti-immunoglobulin (anti-Ig) and T cell--wnditioned medium could induce Ig secretion in rabbit B cells, indicating that two totally antigen­ nonspecific signals (i.e. cross-linking Ig-receptors and T cell-derived helper factors) could induce Ig production in B cells. Subsequently, the results obtained with rabbit B cells were confirmed in the murine system. Parker and his colleagues (4) could induce Ig secretion in murine B cells with in solubilized anti-Ig and culture supernatants of concanavalin A (Con A)­ stimulated T cells. All of these results indicated that the helper function of T cells in antibody response was mediated by soluble factors.

Structure and function of human and murine receptors for IgG.

Abstract: The basic mechanisms by which phagocytes recognize foreign organisms have been known for more than 80 years. In 1903, Wright & Douglas (1) showed that human serum contains heat-stabile and heat-labile factors that bind to the bacteria and thus dramatically enhance the ability of blood phagocytes to ingest Staphylococcus. These factors, IgG and complement, trigger phagocytosis via specific receptors for IgG and complement. Recep­ tors for the Fc portion of IgG (FcyR), play a central role in cellular immune defenses and are, in addition, responsible for stimulating the release of mediators of inflammation and hydrolytic enzymes involved in the patho­ genesis of autoimmune diseases. This review focuses on the current state of knowledge of the structure and function of the heterogeneous family of the FCyRs of mouse and human. The existence of Fc receptors for IgG (FcyR) has been appreciated since the early studies of Berken & Benacerraf (2). However, the recent rapid progress in this field is due in large part to the isolation of monoclonal antibodies (MAbs) specific for different receptors. The FCyR family prob­ ably evolved in parallel with the immunoglobulins; indeed, recent cloning studies (3-5) show that FCyRs form a subgroup of the immunoglobulin supergene family. The FCyRs provide a crucial link between the phagocytic effector cells and the lymphocytes that secrete Ig, since the macro­ phage/monocyte, polymorphonuclear leukocyte, and NK cell FCyRs confer an element of specific recognition mediated by IgG. Phagocytic cells thus have several recognition mechanisms whereby friend can be distinguished

The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens.

Abstract: T cells with V beta 3+ alpha beta receptors are deleted by self-tolerance in mice with particular major histocompatibility complex/self-antigen combinations. This also occurs for other V beta elements. Polymorphism in the major histocompatibility complex and/or the self-antigens that cause massive deletion of T cells using particular V beta elements may be maintained by the need to balance the advantage of a diverse T-cell repertoire against the potential involvement of those elements in autoimmune disease.

Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs.

Abstract: To investigate the effect of persistent HIV infection on the immune system, we studied leukocyte functions in 14 asymptomatic homosexual men (CDC group II/III) who were at least two years seropositive, but who still had normal numbers of circulating CD4+ T cells. Compared with age-matched heterosexual men and HIV-negative homosexual men, the CD4+ and CD8+ T cells from seropositive men showed decreased proliferation to anti-CD3 monoclonal antibody and decreased CD4+ T-helper activity on PWM-driven differentiation of normal donor B cells. Monocytes of HIV-infected homosexual men showed decreased accessory function on normal T cell proliferation induced by CD3 monoclonal antibody. The most striking defect in leukocyte functional activities was observed in the B cells of HIV-infected men. B cells of 13 out of 14 seropositive men failed to produce Ig in response to PWM in the presence of adequate allogeneic T-helper activity. These findings suggest that HIV induces severe immunological abnormalities in T cells, B cells, and antigen-presenting cells early in infection before CD4+ T cell numbers start to decline. Impaired immunological function in subclinically HIV-infected patients may have clinical implications for vaccination strategies, in particular the use of live vaccines in groups with a high prevalence of HIV seropositivity.

Stress proteins are immune targets in leprosy and tuberculosis.

Abstract: To understand the immune response to infection by tuberculosis and leprosy bacilli and to develop improved vaccines, the nature of antigens that are involved in humoral and cell-mediated immunity was investigated. We have determined that five immunodominant protein antigens under study are homologues of stress proteins. This finding and observations with other pathogens suggest that infectious agents may respond to the host environment by producing stress proteins and that these proteins can be important immune targets. We postulate that abundant and highly conserved stress proteins may have "immunoprophylactic" potential for a broad spectrum of human pathogens.

Soluble CD4 molecules neutralize human immunodeficiency virus type 1.

Abstract: Human immunodeficiency virus (HIV) infection can bring about total collapse of the immune system by infecting helper T lymphocytes which express CD4, the molecule which mediates interaction between the cell surface and viral envelope glycoprotein gp120 (refs 3-10). HIV apparently escapes the effects of neutralizing antibodies in vivo by generating new variants which must still interact with CD4 to maintain a cycle of infection. One route to block HIV infection, therefore, could use solubilized CD4 protein to inhibit attachment of the virus to its target cell. We have used recombinant DNA techniques to generate soluble forms of CD4, and show here that these are potent inhibitors of HIV infection in vitro.

Immunology: A Short Course

Abstract: About the Authors, xvii Contributors, xviii Preface and Acknowledgments, xix 1 OVERVIEW OF THE IMMUNE SYSTEM, 1 2 ELEMENTS OF INNATE AND ACQUIRED IMMUNITY, 11 3 IMMUNOGENS AND ANTIGENS, 29 4 ANTIBODY STRUCTURE AND FUNCTION, 41 5 ANTIGEN-ANTIBODY INTERACTIONS, IMMUNE ASSAYS, AND EXPERIMENTAL SYSTEMS, 61 6 THE GENETIC BASIS OF ANTIBODY STRUCTURE, 81 7 BIOLOGY OF THE B LYMPHOCYTE, 93 8 ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX IN THE IMMUNE RESPONSE, 107 9 BIOLOGY OF THE T LYMPHOCYTE, 125 10 ACTIVATION AND FUNCTION OF T AND B CELLS, 141 11 CYTOKINES, 165 12 TOLERANCE AND AUTOIMMUNITY, 183 13 COMPLEMENT, 205 14 HYPERSENSITIVITY: TYPE I, 221 15 HYPERSENSITIVITY: TYPES II AND III, 237 16 HYPERSENSITIVITY: TYPE IV, 247 17 IMMUNODEFICIENCY DISORDERS AND NEOPLASIAS OF THE LYMPHOID SYSTEM, 255 18 TRANSPLANTATION, 285 19 TUMOR IMMUNOLOGY, 299 20 RESISTANCE AND IMMUNIZATION TO INFECTIOUS DISEASES, 313 Glossary, 337 Appendix: Partial List of CD Antigens, 365 Index, 369

The major Fc receptor in blood has a phosphatidylinositol anchor and is deficient in paroxysmal nocturnal haemoglobinuria.

Abstract: Fc receptors on phagocytic cells in the blood mediate binding and clearance of immune complexes, phagocytosis of antibody-opsonized microorganisms, and potently trigger effector functions, including superoxide anion production and antibody-dependent cellular cytotoxicity. The Fc receptor type III (Fc gamma R III, CD 16), present in 135,000 sites per cell 1 on neutrophils and accounting for most of FcR in blood, unexpectedly has a phosphatidylinositol glycan (PIG) membrane anchor. Deficiency of Fc gamma R III is observed in paroxysmal nocturnal haemoglobinuria (PNH), an acquired abnormality of haematopoietic cells affecting PIG tail biosynthesis or attachment, and is probably responsible for circulating immune complexes and susceptibility to bacterial infections associated with this disease. Although a growing number of eukaryotic cell-surface proteins with PIG-tails are being described, none has thus far been implicated in receptor-mediated endocytosis or in triggering of cell-mediated killing. Our findings on the Fc gamma R III raise the question of how a PIG-tailed protein important in immune complex clearance in vivo and in antibody-dependent killing mediates ligand internalization and cytotoxicity. Together with our results, previous functional studies on Fc gamma R III and Fc gamma R II suggest that these two receptors may cooperate and that the type of membrane anchor is an important mechanism whereby the functional capacity of surface receptors can be regulated.

The function of human intercellular adhesion molecule‐1 (ICAM‐1) in the generation of an immune response

Abstract: Monoclonal antibody RR 1/1 directed against the putative LFA-1 ligand molecule intracellular adhesion molecule-1 (ICAM-1) was found to inhibit the T cell proliferative response to the antigen PPD. Interestingly, the percentage of unstimulated monocytes which expressed ICAM-1 on their surface appeared to vary greatly from person to person although the majority of monocytes did express high levels of ICAM-1 within their cytoplasm and surface expression could be rapidly induced on most cells by adherence to fibronectin. Resting T cells showed no evidence of surface or cytoplasmic ICAM-1 although expression was induced both within the cell and on the membrane as a result of activation with phytohemagglutinin or a combination of OKT3 and phorbol 12,13-dibutyrate. The significance of these findings with respect to the function of monocyte and T cell in the generation of an immune response is discussed.

Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T–T cell interactions

Abstract: Down-regulatory phenomena have been described in several experimental models of tissue-specific, T-cell-mediated autoimmunity. For example, resistance to active induction of experimental autoimmune encephalomyelitis (EAE) can be induced by pretreating animals with non-pathogenic inocula of autoantigen1 or effector cells2,3. Moreover, animals that have recovered from one EAE episode are resistant to subsequent induction of EAE4–6. In some models, resistance to EAE has been transferred with immune cells to naive recipients7–12. These experiments, which were based on transfers of unseparated immune cell populations, are difficult to intepret. Immune suppression circuits are known to be complex and involve various distinct cellular subsets13. To further complicate the issue, resistance to EAE can be transferred not only by suppressor cells, but also by encephalitogenic effector cells injected in 'subclinical' doses2,12. We describe now the isolation of homogenous T lymphocyte lines from the spleens of Lewis rats that had recovered from T-cell-mediated EAE (tEAE) caused by the MBP-specific T cell line SI. These spleen-derived T line cells express the CDS phenotype and specifically respond to determinants on the inducing SI line, but not to the autoantigen MBP. Furthermore, the anti-Si cells selectively lyse the encephalitogenic SI T line in vitro and efficiently neutralize their encephalitogenic capacity in vivo.

Heterophilic antibodies: a problem for all immunoassays.

Abstract: We verified that antibody-binding substances in serum that interfere in two-site immunoassays involving murine antibodies are heterophilic antibodies. Incubation of serum containing heterophilic antibodies and a murine monoclonal antibody to human choriogonadotropin (hCG) leads to formation of a series of soluble immune complexes. We investigated the recognition of hCG by reagent antibody in the presence of heterophilic antibodies and found this recognition to be diminished. Consequently, about 30% of serum samples containing heterophilic antibodies falsely appear to contain increased concentrations of hCG. The effect on analyte recognition probably results from steric inhibition of hCG binding to complexed antibody. Heterophilic antibodies detected with a murine antibody also bound immunoglobulin from several other species but did not bind all of those tested.

Destruction of Rat Islet Cell Monolayers by Cytokines: Synergistic Interactions of Interferon-γ, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1

Abstract: An assay was developed to detect the cytotoxic effects of cytokines on rat pancreatic islet cells in monolayer culture. Cell lysis was detected by a 51Cr-release assay after 4 days of incubation with various cytokines. When tested alone, murine (rat and mouse) interferon-gamma (mIFN-gamma) produced a small dose-dependent lysis of islet cells; human IFN-gamma, mouse IFN-alpha/beta, interleukins 1 and 2 (IL-1 and IL-2), tumor necrosis factor (TNF), and lymphotoxin (LT) were inactive. When added together, the following combinations of cytokines showed synergistic cytotoxic effects: TNF (or LT) plus IL-1, TNF (or LT) plus mIFN-gamma, and IL-1 plus mIFN-gamma. These results indicate that the cytokine products of mononuclear cells of the immune system, IFN-gamma, TNF, LT, and IL-1 have strong synergistic cytotoxic effects on islet cells and therefore may act as direct chemical mediators of islet beta-cell destruction in type I (insulin-dependent) diabetes.

Characterization of a renal tubular epithelial cell line which secretes the autologous target antigen of autoimmune experimental interstitial nephritis

Abstract: Proximal tubular epithelial cells from mice which develop autoimmune interstitial nephritis were found to express the nephritogenic target antigen, 3M-1. Anti-3M-1 mAbs (alpha 3M-1-Ab) were used to positively select for 3M-1-secreting tubular epithelium and, after stabilization in culture, this new cell line (MCT) was examined for the production of several moieties important to either immune interactions or to the development of extracellular matrix. Alkaline phosphatase-staining MCT cells also express epithelial growth factor receptors with a Kd of 0.87 nM and an epithelial growth factor receptor constant (Ro) of 2.1 X 10(4) receptors/cell. MCT culture supernatants contain greater amounts of laminin, and types IV and V procollagens compared to types I and III procollagens, and growing MCT cells on type I collagen matrix causes them to preferentially secrete even more type IV and V procollagen. The 30,000-Mr 3M-1 antigen could be immunoprecipitated from biosynthetically labeled MCT cell supernatants with alpha 3M-1-Ab. An identical-sized moiety was isolated by immunoaffinity chromatography from collagenase-solubilized mouse kidney tubular basement membranes. The 3M-1 antigen can be found on the MCT cell surface by radioimmunoassay, or deposited in a linear array in the extracellular matrix surrounding the MCT cells in culture by immunofluorescence. Mature messenger RNA species for both class I and class II major histocompatibility complex (MHC) molecules were detected by Northern hybridization, and their corresponding cell surface gene products were detected by cytofluorography of MCT cells stained with haplotype-specific antibodies. Both the cell surface 3M-1 and the small amounts of detected class II MHC molecules appear to be biologically functional, as MCT cells can support the proliferation of 3M-1-specific, class II MHC-restricted helper T cells in culture. These findings suggest that MCT cells provide all the necessary biological parameters for interfacing both as the target of a nephritogenic immune response, and as a potential source for new extracellular matrix which develops as a fibrogenic response to interstitial nephritis.

Biologically diverse molecular variants within a single HIV-1 isolate.

Abstract: AIDS is a disorder characterized by a slow progressive impairment of immune function and by infection of human immunodeficiency viruses (HIV-1, HIV-2)1–4. Our knowledge of how these viruses cause disease in man, or how the related lentiviruses (visna and equine infectious anaemia virus) cause disease in animals, is still fragmentary. In particular, the significance of genetic variation in HIV-1, occurring within populations, within individuals and over periods of time5,6, and the mechanisms of viral persistence remain unclear. To address these issues we prepared a series of proviral clones of HIV-1 originating from a single patient and compared their biological properties. Here we show that hybrid genomes (in which the envelope region of six viral clones were separately substituted into a prototype HIV-1 genome) generated viruses with widely differing capacity to grow in human T cells, cell lines and monocytoid cultures. These data suggest that extensive biological variation exists in vivo within an infected individual and is in part determined at the level of the viral envelope.

Receptor-directed focusing of lymphokine release by helper T cells.

Abstract: The interaction between helper T cells and B cells, leading to the production of antibody to thymus-dependent antigens, was the first cell interaction clearly defined in the immune system1–3; it remains both paradigmatic and controversial. Two requirements of this interaction, that the helper cell (TH) and the B cell must recognize antigenic determinants that are physically linked4,5, and that the TH and the B cell must share genes encoding major histocompati-bility complex (MHC) class II molecules6, led to the concept that TH–B interaction required an intimate physical association of the two cell types. But in vitro studies have shown that TH can be replaced by soluble, antigen-nonspecific factors, capable of activating any B cell to secrete antibody7,8. We have previously proposed that the requirements for TH–B contact might result from TH cells releasing their lymphokines in a polar fashion directed at that portion of the cell membrane where T-cell receptor cross-linking is actually occurring9–16. Using an artificial monolayer of a cloned helper T-cell line, we show that lymphokines are r eleased preferentially over the area of receptor cross-linking under conditions of limited TH-cell activation. Thus, it appears that one important aspect of the specificity of TH–B cell interactions is the receptor-directed polar release of helper lymphokines.

Age-related galactosylation of the N-linked oligosaccharides of human serum IgG.

Abstract: In a study of 151 normal, healthy individuals of both sexes varying in age from 1-70 yr, it was found that the relative incidence of agalactosyl (with both outer arms terminating in N-acetylglucosamine) N-linked oligosaccharides on total serum IgG decreased from birth to a minimum (at 25 yr of age) and then increased with age. The relative incidence of digalactosyl structures varied inversely to this, and the relative incidence of monogalactosyl structures was constant. Galactosylation of the N-linked oligosaccharides of the human serum IgG of normal individuals is therefore an age-related molecular parameter. Several reports have suggested that rheumatoid arthritis is associated with a decreased galactosylation of serum IgG (3-5). The normal variation in galactosylation with age as described here allows a true assessment of disease-associated changes in this parameter, and raises the possibility that one of the lesions in rheumatoid arthritis is an accelerated aging of the immune system. In addition, heterogeneity within age groups may be due to intrinsic differences in genetic endowment, or may reflect the impact of extrinsic factors (8).

Oral Salmonella typhimurium vaccine expressing circumsporozoite protein protects against malaria.

Abstract: Immunization with radiation-attenuated malaria sporozoites induces potent cellular immune responses, but the target antigens are unknown and have not previously been elicited by subunit vaccines prepared from the circumsporozoite (CS) protein. A method is described here for inducing protective cell-mediated immunity to sporozoites by immunization with attenuated Salmonella typhimurium transformed with the Plasmodium berghei CS gene. These transformants constitutively express CS antigens and, when used to immunize mice orally, colonize the liver, induce antigen-specific cell-mediated immunity, and protect mice against sporozoite challenge in the absence of antisporozoite antibodies. These data indicate that the CS protein contains T cell epitopes capable of inducing protective cell-mediated immunity, and emphasize the importance of proper antigen presentation in generating this response. Analogous, orally administered vaccines against human malaria might be feasible.

HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals

Abstract: Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.