Showing papers in "Immunological Reviews 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.

The preparation and cytotoxic properties of antibody-toxin conjugates.

Abstract: L INTRODUCTION Interest has burgeoned recently in the possibility of attacking tumor ceils with cytotoxic agents covalently linked to specific antibodies. This follows the innovation of cell hybridization techniques for producing monoclonal antibodies which has stimulated a world-wide search for antibodies with specificity for cancer cells. In anticipation that these endeavors will meet with success, a number of groups have attempted to devise ways of arming the antibody molecule to endow it with potent cytotoxic activity against the cells to which it can bind. Our decision to use toxins as the cytotoxic component ofthe conjugate was provoked by their supreme potency. One molecule of the bacterial exotoxin, diphtheria toxin, or of the plant toxins, abrin, from Abrus precatorius or ricin, from Ricinus communis, may be sufficient to kill a cell which it penetrates (Yamaizumiet al. 1978, Eiklid et al. 1980). This maximizes the chance of killing cancer cells which do not express specific antigens at high density or which reside in solid tumors not freely permeable to the conjugate. The modes of cytotoxic action of diphtheria toxin, abrin and ricin have been reviewed elsewhere (Collier 1976, Olsnes & Pihl 1976, Pappenheimer 1977, Gill 1978). Briefly, the toxins ali comprise two polypeptide chains, denoted A and B, which are linked by a disulfide bond and which, when separated, are virtually devoid of cytotoxic action. The toxins bind via a recognition site on the B-chain to receptors on the cell surface and the A-chain then penetrates (or is translocated across) the cell membrane into the cytosol where it terminates protein synthesis. Diphtheria toxin A-chain inactivates elongation factor 2 by

Interleukin l and T Cell Activation

Abstract: The antigen-specific activation of T cells is dependent upon two distinct but interdependent macrophage signals. Macrophages are required to bin^, process, and present antigens in an immunogcnic form to T cells (Schwartz et ul. 1978). This function of the macrophage is genetically-restricted and is a property of an la positive subpopulation of macrophages. The second macfophage-derived T cell activating signal is a Iow molecular weight antigen-non-specific peptide termed interleukin 1 (IL I) (Aarden et al. 1979) that is apparently produced by all macrophages (Oppenheim etal. 1979). As will be discussed in this review, IL I appears to act as a maturational signal, preparing T cells to respond to antigens or secondary mediator signals. One of the major activities of interleukin 1 is to induce the synthesis and secretion of the T cell-derived mitogenic lymphokine, interleukin 2 (IL2) (Farrar et al. 1980b, Smith et al. 1980, Larsson et al. 1980). This link between IL 1 and IL 2 is an essential element in the T cell activation sequence because it involves the conversion of a primary macrophage-derived maturational signal into a secondary T cell-derived proliferative signal that results in the amplification of specific immune responses.

The biochemistry, biology, and role of interleukin 2 in the induction of cytotoxic T cell and antibody-forming B cell responses.

Abstract: Interleukin 2 (IL 2) (Aarden et at. 1979) is a genetically unrestricted, soluble immunoenhancing factor which is produced by helper T cells following stimulation with either T cell mitogens or allogeneic cells. Presumably, IL 2 is also produced and secreted following specific antigen stimulation, although this question has not been carefully evaluated. The definitive biological assay for IL 2 measures the factor's ability to maintain the growth of factor-dependent cytotoxic T cell lines. However, a broad spectrum of biological activities has been ascribed to IL 2. The factor has been reported to induce thymocyte proliferation either in the presence (Chen & DiSabato 1976, Paetkau et al. 1976) or absence (Farrar et al. 1978) of a suboptimal concentration of T cell mitogen. Additionally, IL 2 has been shown to augment the proliferation and generation of cytotoxic cells by alloantigenstimulated T cell populations (Wagner & Rollinghoff 1978, Farrar et al. 1978) and, in the process, induce the synthesis of immune interferon (IFNji) by the alloantigen-stimulated T cells (Farrar et al. 1981a). IL 2 has also been reported

Immunotoxins: hybrid molecules combining high specificity and potent cytotoxicity.

Abstract: Biological activities of enzymes, hormones or antibodies are induced only after recognition of their specific targets. This selective activity is obtained in Nature with molecules which possess at least two different functions, recognition and biological activity, in general performed by different domains of the same molecule. Specificity of antibody activity is obtained by the sequential involvement, first of the binding unit, which then activates the effector function, i.e. complement-binding antibodies only activate the complement system and destroy target cells if they are first bound to their specific antigen. The idea of applying specific cell lysis by antibodies to passive immunotherapy of tumors has been very attractive for many years. However, the capacity of antibodies to destroy tumors in animals or man has always been limited, and it has often been observed that specific antibodies can enhance tumor growth (enhancement phenomenon). As a result, a series of attempts have been made to render the effector function of antibodies more potent by attaching either anticancer agents to these antibodies, a tentative step first described by Mathe et al. (1958), or toxins, as initiated by Moolten & Cooperband (1970). Higher potency, however, will only be beneficial for tumor therapy if it is specific for the target tissue, in the sense that the effector function

LFA-1 and Lyt-2,3, Molecules Associated with T Lymphocyte-Mediated Killing; and Mac-1, an LFA-1 Homologue Associated with Complement Receptor Function1

Abstract: Killer cells are an important component in the immune response to cells with altered or foreign cell surface antigens. Antigen-specific killing is mediated by a subset of Thy-T thymus-derived (T) lymphocytes which have been termed cytolytic T lymphocytes (CTL). CTL can be elicited in response to allogeneic or xenogeneic cells bearing foreign histocompatibility antigens, or in response to syngeneic cells bearing foreign antigenic determinants introduced by chemical haptenation or viral infection (reviewed in Engers & MacDonald 1976, Golstein 1976, Martz 1977, Henney 1977, Berke 1980, Burakoff et al. 1980). Inductionof maximal cytolyticactivity requires 5 to 10 days for a primary response. Cytolytic activity displays all the hallmarks of specific immunity, i.e. it is highly specific for antigens on the eliciting cells, and it shows accelerated development and reaches

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.

HLA-DR antigens: structure, separation of subpopulations, gene cloning and function.

Abstract: The hutnan major histocompatibility complex, called the HLA region, is located on the short arm of chromosome 6. To date this region is known to code for about six proteins expressed on the cell surface and several serum complement factors. The HLA region could accomodate the structural genes for many more proteins. The HLA-controlled cell surface antigens are highly polymorphic both serologically and structurally. This polymorphism is essential for the function of these molecules which, evidence indicates, is to allow ceils of the immune system to discriminate self from non-self.

Mechanism of T cell activation: role and functional relationship of HLA-DR antigens and interleukins.

Abstract: The recognition that supernatants of mitogen activated (Morgan et al. 1976, Gillis & Smith 1977) or mixed leukocyte cultures (Ryser et al. 1978) contain a T .• cell growth factor (TCGF, now termed InterIeukin-2, Aarden et al. 1979) that i supports the continuous growth and proliferation of human and murine T cells has allowed both the expansion of T lymphocyte populations and the cloning of cells belonging to functionally disparate subpopuiations. Numerous studies have shown that antigen-specific or non-specific murine fl|: and human cytotoxic, suppressor as well as helper T lymphocytes can be maintained in a state of continuous proliferation in vitro when cultured in medium containing Interleukin-2 (11-2) (Gillis & Smith 1977, Alvarez et al. 1978, Kurn i cke t a l . 1979, von Boehmer et al. 1981, Bach et al. 1981, Glasebrook e ta l . 1981, Schreier et al. 1980, Watson 1979, Apte et al. 1981, Kurnick e t a l . 1981, Fathman & Kimoto 1981, Sarmiento et al. 1980, Sredni & Schwartz 1981). Several research groups have shown that 11-2 does not support growth of nonJj\" ^ activated T lymphocytes. Thus, it has been postulated that a T cell population must be \"activated\" both to become sensitive to 11-2 and to produce this growth factor in order to proliferate (for review see Moller 1980). Due to the welldocumented macrophage requirement for mitogen induced II-2 production (Smith et al. 1980) and the observation that Interleukin-1 (Il-l , previously ,, I • referred to as lymphocyte activating factor or L A F (Aarden 1979)) is a . j' macrophage product (Gery et al. 1972, Mizel et al. 1978), it has been hypothesized that II-1 may be an essential signal required by 11-2 producer T cells (Smith et al. 1979, 1980, Farrar et al. 1980, Larsson et al. 1980). Although the involvement of II-1 in the production of II-2 by ligand-stimulated T cells appears unquestionable, the precise mechanism by which II-1 functions in this capacity

Cloned T Lymphocytes and Monoclonal Antibodies as Probes for Cell Surface Molecules Active in T Cell‐Mediated Cytolysis

Abstract: The appearance of specific cytolytic T lymphocytes (CTL) is a prominent feature of cell-mediated immune responses to viral infections and to aliografts. CTL kill their target cells through a process consisting of at least three steps: (1) antigen recognition and celhceil adherence, (2) a Ca^-dependent lethal hit, and (3) target cell death. The highly specific nature of the antigenic recognition observed in T cell-mediated cytolysis indicates that a discriminating antigenreceptor molecule must be Involved, but attempts to identify this T cell receptor have met with only limited success. In addition to an antigen-specific receptor, other cell surface molecules appear to participate in the cytoiytic process. Antisera reactive with cell surface components have been utilized in attempts to define the molecules involved in cytolysis. Several investigators (Nakayama et al. 1979, Shinohara & Sachs 1979) demonstrated that anti-Lyl-2 alloantisera couid inhibit cytolysis mediated by T cells obtained from immunized animals or from mixed lymphocyte cultures (MLC). However, the interpretation of these results was complicated by the fact that such antisera may have contained antibodies which reacted with other antigens. In addition, it was difficult to be

Clonal Heterogeneity in the Functional Requirement for Lyt-2/3 Molecules on Cytolytic T Lymphocytes (CTL): Possible Implications for the Affinity of CTL Antigen Receptors

Abstract: Despite extensive investigation over the past decade, the mechanism of target cell lysis by cytolytic T lymphocytes (CTL) remains obscure (for recent reviews, see Perlmann & Cerottini 1979, Berke 1980). Since lysis is known to require close contact between CTL and target cells, one promising approach to this problem is the search for surface molecules on CTL which may play a role in antigen recognition and/or the expression of cytolytic activity. With the recent availability of monoclonal antibodies, it has become possible to identify such potentially interesting surface molecules by virtue of the ability of a corresponding monoclonal antibody to block CTL activity in the absence of complement. Using such an approach, two possible \"functional\" molecular complexes on CTL populations have been recently identified: Lyt-2/3 (Nakayama et al. 1979, Shinohara et al. 1979) and LFA-1 (Davignon et al. 1981). At least two limitations to the interpretation of these antibody blocking experiments can be invoked. Firstly, blocking was carried out on polyclonal CTL populations activated by lectins or alloantigens; thus it is not possible to

Cyclosporin A--usefulness, risks and mechanism of action.

Abstract: Very little new happened in the field of immunosuppression after the discovery of azathioprine in the early 'sixties (Schwarz et al. 1959). Admittedly, there has been the introduction of heterologous antilymphocyte serum (Starzl et al. 1967), which to some extent has become a part of the regular therapeutic regimen in organ transplantation. Other than that, very little that could stop an immune response has been brought forward by the immunologists during these two past decades. Nevertheless, the understanding of immune functions has advanced a great deal during that same period, although in terms of immunosuppression the transplant surgeons were left with the old, but not so effective combination of steroids, azathoprine and somewhat later anti-lymphocyte serum (that, indeed, they still use). But a new drug is rapidly invading the market. That is cyclosporin A (CyA), which is the scope of this review. Although it was detected nearly 10 years ago (Borel 1976), it is still new as it is presently being scrutinized in clinical trials in man and is thus not commonly in use yet. In most countries it has as yet only been used for very limited purposes. The attraction of this compound is multifold, but one feature is that, unlike all other immunosuppressants, tentative mechanisms of action for it have been brought forward based on interpretable experimental data. This is, we think, why a review of the present state of knowledge on cyclosporin A is warranted. The drug has already been admirably analyzed in these reviews (Calne 1979), but much relevant information on it has accumulated since then.

Antigen presentation by vascular endothelial cells and epidermal Langerhans cells: the role of HLA-DR.

Abstract: T and B lymphocytes apparently recognize antigen in two fundamentally different ways. B cell receptors (antibodies) can bind directly to free antigen, whereas the T cell receptor binds to antigen and cell surface markers on specialized accessory cells, generally designated antigen presenting cells. In humans these cell surface markersof importance for antigen activation of T cells are polymorphic membrance glycoproteins: the Class II HLA-DR molecules {Bergholtz & Thorsby 1977, Hansen et al. 1978, Hirschberg et al. 1979a), and perhaps the MT group of antigens (Thorsby et al. 1982). Antigen therefore most probably must be presented together in complexed form with Class li molecules on the surface of the antigen-presenting cells for T cell activation to occur. Antigen does not necessarily have to be presented together with self MHC molecules, but in certain experimental situations, only with the MHC products \"seen\" by the T cells at the time of initial sensitization (Thomas & Shevach 1977, Ishii et al. 1981). Additionally, after T cell binding to antigen-MHC complexes in the cell membrane, the antigen-presenting ceil produces a soluble Iymphokine now defined as Interleukin I (Il-I) which is necessary for futher T cell proliferation and differentiation (Blyden & Handschumacher 1977, Smith et al. 1980).

Molecular Characterization of Interleukin 2

Abstract: The isolation of specific T cell growth factors termed interleukin 2 (IL 2) is changing the approach to understanding T cell function. This class of growth factors has allowed te establishment of a number of human and murine T cell lines. We summarize the biochemical properties of human and murine IL 2. Studies have been initiated to isolate mRNA encoding for IL 2. Such RNA can be translated in rabbit reticulocyte lysates yielding IL. 2. This RNA may be useful for the development of probes to isolate lymphokine genes.

Lymphoid cell surface interaction structures detected using cytolysis-inhibiting monoclonal antibodies.

Abstract: We screened monoclonal antibodies obtained by xenogeneic immunization for their capacity to inhibit T cell-mediated cytolysis. These antibodies fell into two classes according to the cell structures they recognized, of 30-35 K and 94-180 K apparent molecular weight, respectively. The main features of these structures and of their interaction with the corresponding antibodies were reviewed. The inhibition of cytolysis by these antibodies was shown to occur mainly at the effector cell level, at the recognition stage of cytolysis, and to depend on the nature of target cells, effector cells, and link between these cells. T cell functions other than cytolysis were also inhibited by some of these antibodies. We considered various possible mechanisms to account for the inhibition of cytolysis by these mAb. We favor an hypothesis based on inhibition by these mAb of lymphoid cell surface interaction structures. This hypothesis was discussed within the general framework of cell interaction structures in immunological and non-immunological experimental systems.

Interleukin 3: Possible Roles in the Regulation of Lymphocyte Differentiation and Growth

Abstract: Much of the regulation of lymphocyte differentiation is unknown. This, in part, has been due to the inability to develop reliable in vitro assays or long-term cultures of lymphocytes. Consequently, many of the current hypotheses concerning the pathways and regulation of lymphocyte differentiation were obtained from complex in vivo experiments. During recent years, however, new techniques and concepts have evolved which may ultimately allow a critical in vitro dissection of the events in lymphocyte differentiation. The concept that lymphokines, as identifiable and purifiable proteins, mediate reactions that were once attributed to complex cell interactions provides a much more amenable approach for ultimate resolution of the basic biology involved. The observation that certain lymphokines have the capability of supporting the proliferation and growth of specific lymphocytes in vitro as an integral component of their physiological functions provides the unique opportunity to isolate specific intermediates in lymphocyte differentiation. The extent to which these approaches will be capable of unraveling the relationship of various lymphocyte subpopulations is unknown, although the available evidence suggests that the principles thus far established may be central to the regulation of immune responses and consequently may be broadly applicable. In this review, the biology and biochemistry of interleukin-3 (IL-3) are discussed. Many of the properties of lL-3 are similar to lL-2 in that they promote differentiation and are required for growth by various lymphocyte lines. However, unlike lL-2, lL-3 appears to primarily influence a stage or stages of immature lymphocyte differentiation and, therefore, provides the means to dissect in vitro a completely unique aspect of lymphocyte differentiation.

Immunity to Asexual Erythrocytic Stages of Plasmodium Falciparum: Role of Defined Antigens in the Humoral Response1

Abstract: Malaria, a widespread disease of man and other vertebrates, is caused by a unicellular protozoan of the genus Plasmodium and is transmitted by the bite of female Anopheline mosquitoes. Among the four species which infect man, Plasmodium falciparum is by far the most lethal. The pathological consequences of malaria, characterized by febrile paroxysms, anemia, splenomegaly and debilitation, are due to the development and proliferation of asexual erythrocytic stages in the vertebrate host. A major public health problem in the world today, malaria presents a serious threat to economic and social development in large tropical and subtropical areas. More than one billion people live in endemic areas, over 200 million suffer from malaria and it is estimated that a million children under the age of 14 die annually from this disease in Africa alone (WHO 1976).

Effector mechanisms of immunity to schistosomes and their regulation.

Abstract: Increasing interest has been shown, during the last decade, in the study of immune mechanisms of defense against various parasites. Among the parasites which have been most widely used as models, schistosomes have been employed in a broad experimental approach which has illustrated the existence, among the immunological components of the specific response to metazoan parasites, of novel effector and regulatory mechanisms. Schistosomiasis, an infection which affects 300 million people in the world, is characterized by the presence of adult worms in the portal and mesenteric veins of man and various other mammalian species, as part of a complex migratory cycle initiated by the cutaneous penetration of water-living infective cercariae. These transform into schistosomula under the skin of appropriate hosts. It is generally agreed that pathological reactions to schistosome infection are related to the deposition of numerous eggs of the parasite in host tissues (Warren 1968). Although clinical studies have made possible the investigation of several immune mechanisms operating in man, most of information has been derived from the use of various experimental models, among which the mouse and the rat have been the most widely used. Rat infection by schistosomes deserves particular mention. In this rodent experimental infection by cercariae results in the establishment of a worm population which is almost entirely rejected 3 to 4 weeks after the initial challenge, this rejection being itself followed by a strong and prolonged immunity to reinfection. Many experimental observations, supported by epidemiological evidence in man, have pointed to the invasive larval stage of the parasite, i.e. schistosomulum, as the main target of immunity, while the adult population seems relatively unaffected by immune effector mechanisms (i.e. concomitant immunity) (Smithers & Terry 1969).

Monoclonal antibody-ricin or ricin A chain hybrids: kinetic analysis of cell killing for tumor therapy.

Abstract: In 1977 this laboratory proposed the construction of a new class of cell type specific cytotoxic reagents to be prepared by altering the receptor specificity of toxins. As originally conceived the binding chain of a toxin, such as ricin or diphtheria toxin, was to be replaced by a new binding moiety which would direct enzymatically active toxin A chain into a unique cell population having receptors for the modified toxin. Theoretical considerations indicated that such hybrid toxins might display cell type selectivities as high as 10'* —10\\ It was proposed that these reagents would be useful for cell-type-specific cancer chemotherapy. The original paper outlined the methodology for achieving high yields of hybrid proteins free of homopolymers, consisting of placing differing chemical reactive species on the two proteins (Chang & Neville 1977). The efficacy of the earliest hybrid toxins constructed with peptide hormones as the new binding chain was poor. Chang et al. (1977) were unable to demonstrate toxicity of a human placental lactogen disulfide linked diphtheria toxin A chain hybrid even though the binding function and the A chain enzymatic activity remained intact. Oeltman & Heath (1979) demonstrated cell type specific cytotoxicity for the hybrid chorionic gonadotrophin-S-S-Ricin A chain, however the potency was less than the parent toxin by a factor of 800. A variety of A chain hybrids were constructed utilizing lectins {Uchida et al. 1980, Gilliland et al. 1978) or antibodies (Masuho et al. 1979, Gilliland et al. 1980) as binding chains. These hybrids all exhibited reduced potency relative to the parent toxin. Recently, however, several A chain hybrids have been constructed

Molecules on the surface of parasitic nematodes as probes of the immune response in infection.

Abstract: Metazoan parasites are the most complex of human pathogens and of these the nematodes are a most ubiquitous yet diverse phylum. These roundworm parasites constitute an enormous medical and veterinary burden in many parts of the world, and as a public health problem are most severe in tropical countries. The numbers of individuals infected with nematodes such as hookworm, Ascaris or those causing filariasis run into hundreds of millions (Muller 1975), and yet our understanding of how these parasites successfully invade the host is still at an early stage. Nematodes evoke a full spectrum of immunological responses {Mitchell 1979, Ogilvie 1979) yet in many infections immunity is insufficient, or even misdirected to an extent which permits parasite establishment and long persistence. Indeed, the host's immune response may by quite inappropriate, and the pathogenic consequences of over-vigorous responsiveness are illustrated by elephantiasis in filarial infections. It is clear, however, that in many instances of successful parasite rejection by the host there is an excess capacity to eliminate, with an overlap of mechanisms which ensures immunity (Wakelin 1978, Haque et al. 1980, Miller 1980). The persistent parasite must therefore circumvent a number of barriers and doubtless has evolved the ability to use a series of evasive or diversive manoeuvres during its development. Over the course of a nematode infection immunity can act at many different stages. There is often a rapid response to the invading larvae, particularly if reinfection is occurring {Ogilvie & Jones 1971, Love & Ogilvie 1975,Chiacumpa

The Secret of the Immunopathogenesis of Schistosomiasis: IN VIVO Models

Abstract: The opportunity afforded by Immunological Reviews to summarize my \"own work without necessarily reviewing the entire literature in the field\" is particularly appropriate at this time because these investigations began 25 years ago with the discovery of a murine model of hepatosplenic schistosomiasis. At the Laboratory for Tropical Diseases ofthe National Institutes of Health in Bethesda, Maryland, in the laboratory of Dr. William B. DeWitt, it was found that mice with Schistosoma mansoni infections develop hepatomegaly, splenomegaly, esophageal varices, and portal hypertension (Warren & DeWitt 1958). This animal model bore a striking resemblance to descriptions of the clinical syndrome in man, including minimal liver parenchymal cell dysfunction. Using the hepatosplenic disease model, investigations of the pathogenesis of schistosomiasis began with the determination ofthe parasite factor responsible for the syndrome. The suspicion that the host granulomatous response to the parasite eggs was crucial in the pathogenesis of hepatosplenic disease was suggested and later proven through cinemicrophotography. Studies of the immunological etiology ofthe host response did not begin until 10 years after the discovery of the model, a period in which parasitological, pathological, and pathophysiological investigations consolidated its status. The immunological investigations quickly led to the acquisition of strong evidence that the granulomatous lesions were reactions ofthe cell-mediated type. Corroboration was provided by a wide variety of further experiments both in vivo and in vitro. Concurrently, an early observation of endogenous suppression of the host granulomatous response was investigated, revealing a complex immunoregulatory system with profound modulating effects on the disease syndrome. Antigen isolation was facilitated by knowledge of the parasite stage responsible for the disease, the mechanism of the host infiammatory response, and the mechanisms of its modulation.

CBA/N immune defective mice; evidence for the failure of a B cell subpopulation to be expressed.

Abstract: C B A / N mice have an X-linked defect leading to low serum IgM levels, an inability to respond to certain thymus independent (TI) antigens, and low responses to thymus dependent (TD) antigens (Amsbaugh et al. 1972, Scher et al. 1973, 1979). The gene or closely linked genes responsible for the immunologic defects of C B A / N mice have been mapped between the hypophosphatemia {Hyp) and tabby {Ta) genes (Berning et al. 1978). C B A / N mice are a useful experimental model to analyze the development, function, heterogeneity, and interactive properties of B cells (Scher 1981). They have also been useful in studies of the role of lymphocyte functions in infectious (Brown et al. 1977, Quintans 1977, Lucas et al. 1978, O'Brien et al, 1979, 1981, Hunter et al. 1979, Jayawandena et al. 1979, Yother etal. 1981, Lee & Ihle 1981) and autoimmune processes(Izuietal. 1977,Rosenberg l979,Marshall-Clarkeetal. 1979,Kempet al. 1980, Reeves et al. 1981, Taurog et al. 1979, 1981, Romain et al. 1980, Cowdery et al. 1980, Steinberg et al. 1981). The well-known linkage of the Xchromosome and a number of human immune deficiency diseases has provided additional stimulus for a thorough evaluation of the extent and mechanism(s) of the immune deficiencies of C B A / N mice.

Analysis of infection characteristics and antiparasite immune responses in resistant compared with susceptible hosts.

Abstract: Variations in susceptibility or immune responsiveness to parasites, and variations in the consequences of parasitic infection, are readily detected in natural host populations (Wakelin 1978a). Variable outcomes of parasitic infection and disease are predictable bearing in mind that genetic heterogeneity of hosts a«c/parasites is essential for evolutionary survival of either party. It has been argued that immunological events have been the key (but certainly not the only) ingredient in the evolutionary development of balanced host-parasite relationships (Sprent 1959, Burnet & White 1972, and reviewed in Mitchell 1979a,b). The animal breeder expects to exploit any high hereditability of resistance to parasites and searches for linked characteristics which are detected readily, or correlative immune responses, to be used in selection programs. Similarly, the experimental immunoparasitologist expects to exploit at least some genetically-based variations in host resistance to pinpoint immunological effector mechanisms and target parasite antigens (and to identify genetic aspects of expression oi both) which are necessary or sufficient for host protection. Of particular interest are differences in (1) disease manifestations, (2) levels and duration of primary infection, (3) responsiveness to vaccination, (4) responsive-

HLA-D region molecules restrict proliferative T cell responses to antigen.

Abstract: During recent years it has been clearly established that T lymphocyte responses to antigen are restricted by products of the major histocompatibility complex; MHC. Activation of helper T lymphocytes requires co-recognition of antigen and products of the H-2I (class II) region in the antigen-presenting cells (APC) while activation of cytotoxic T cells involves co-recognition of antigen and products of the H-2D,K (Class I) regions in the target cells. Whether the explanation for this phenomenon is T cell recognition of antigen via singlespecificity or double-specificity receptors is still not known (for references see Thomas et al. 1977, Zinkernagel & Doherty 1979). After in vivo sensitization of normal animals, most antigen-specific T cells will be restricted by products of the self MHC; i.e. the MHC of the animal under study. Under particular experimental conditions, however, T cells which are restricted by allogeneic MHC products can also be demonstrated (Thomas & Shevach 1977, Wilson et al. 1977, Ishii et al. 1981). MHC restriction has also been demonstrated for human T cells. Activation of the T helper/amplifier (Th/a) subset requires co-recognition of antigen and products of the HLA-D (Class II) region in the antigen presenting cells (APC), while the cytotoxic T (Tc) cells.are restricted by products of the HLA-ABC (Class I) regions (for references see Thorsby 1982). Here we will summarize some of our own most recent studies on the restriction of proliferative T lymphocyte responses to antigen by HLA-DR and other Class II HLA cell membrane molecules. Peripheral blood mononuclear non-T cells or monocytes/macrophages have been used as APC. Elsewhere in this volume a review is given using as APC other cells expressing Class II molecules; endothelial cells and Langerhans cells (Hirschberg et al. 1982).

Regulation of growth and proliferation in B cell subpopulations.

Abstract: The activation of B lymphocyte subpopulations by anti-immunoglobulin and by LPS has been examined. All resting B cells were stimulated to grow larger (i.e. to go from G0 phase to mid G1 phase of the cell cycle) by the continuous presence of anti-mu antibodies. A subpopulation oif these B cells, 30-50% in normal mouse strains, entered S phase in response to large doses of anti-mu. This subpopulation, probably Lyb5+, was completely absent in mice with the xid-determined immune defect. Another, apparently distinct subpopulation, comprising about 25% of the cells, and probably present in xid mice, was sensitive to a proliferative signal delivered by LPS, if the cells had first been cultured for 24 h in the presence of a dose of anti-mu that was sufficient to cause cell enlargement. The fraction of B cells responding to LPS in this way was significantly larger than the fraction responding to LPS alone, suggesting that anti-mu is superior to LPS at inducing the G0 to G1 transition. Based on these results we propose a model of the control of B cell growth and proliferation. Anti-Ig antibodies, or epitopes on conventional antigens, combine with and cross-link B cell receptors, causing the cells to enter G1 and to develop sensitivity to late G1 stimuli, which determine whether they will then enter S phase. These stimuli are provided either by a high dose of anti-mu or by LPS. These agents may work directly or may stimulate other cells to produce B cell Growth Factor (BCGF) and/or related regulatory molecules which may be the actual late G1 stimuli. Distinct B cell types are sensitive to distinct mechanisms for control of proliferation. A new monoclonal antibody, 14G8, which recognizes only a fraction of B cells (30% in normal mice and about 65% in xid mice), was used to separate B cell subpopulations based on the presence or absence of the cell surface antigen recognized by this antibody. The results suggest that 14G8 expression is negatively correlated with Lyb5 expression, although not absolutely. Indeed 14G8+ B cells respond quite well to anti-mu (32% the cells enter S phase). Since Lyb5- B cells are believed not to proliferate in response to anti-mu, this would suggest that a sizeable fraction of the 14G8+ B cells are also Lyb5+. The 14G8+ and 14G8- B cell subpopulations were found to be functionally distinct in that the former responded very well to LPS, whereas the latter responded very poorly. Models of B cell development based on expression of these membrane antigens are presented.

The Genetic Control of Human Ia Alloantigens: A Three‐Loci Model Derived from the Immunochemical Analysis of ‘Supertypic’ Specificities

Abstract: The complexity ofthe HLA system derives first from the presence of different genes which control similar molecular species and are in close linkage; they probably resulted from gene duplication. Secondly, the complexity derives from the high polymorphism at each locus with multiple-site interallelic differences. A third level of complexity, which is a combination of the first two, is the linkage disequilibrium which preferentially ties some alleles of a locus to some aileles at another locus. This challenging complexity has been attacked by the collaborative efforts of a large number of laboratories over the last 20 years. A large pool of knowledge of the mechanisms of graft rejection, of susceptibility to a number of diseases, and of the immune response in general has resulted from this massive investigation. The classical approach, which is still the core of HLA research, has been the serological study at the cellular level of the alloantigenic specificities possessed by the HLA products; this has been done mainly by the complement-dependent lymphocytotoxicity assay. Through the International Histocompatibility Workshops, this approach led to the recognition of'clusters' of antisera with similar reactivity patterns, thus operationally defining 'antigens'. These antigens were then assigned to different loci, of which genetic distances were determined. Allele frequency in different populations and linkage disequilibrium relationships between alleles at different loci were also defined.

Studies on the mechanisms of immunity in human schistosomiasis.

Abstract: Studies on immunity in schistosomiasis, as in other parasitic infections, have followed two distinct directions: first, the use of experimental animal models, in either natural or unnatural host-parasite combinations; and, secondly, the use of assay systems for studying immune effector mechanisms m vilro. Each of these two approaches, which are not mutually exclusive, has its own advantages and disadvantages. The experimental animal models may permit the identification of effector mechanisms that are demonstrably involved in mediating immunity In vivo. However, there appears to be a wide species variation in host response to schistosome infection (reviewed by Smithers & Terry 1976, Phillips & Colley 1978) and there is no evidence that any experimental animal provides an accurate reflection of the situation in man. In contrast, studies in vilro can provide no direct evidence for the role of various effector mechanisms in vivo. However, they do allow a more precise identification and detailed analysis of each mechanism than would be po.ssibie in vivo: and, more importantly, they can be carried out with human materials, and therefore offer an approach to the study of human immunity.

In vitro and in vivo efficacy of conjugates of daunomycin with anti-tumor antibodies.

Abstract: Chemotherapy constitutes a major therapeutic approach for the treatment of cancer, alongside surgery, radiotherapy and, to a lesser extent, immunotherapy, non-specific or specific. The advantage of chemotherapy as compared with surgery and radiotherapy is that it can be used effectively for disseminated as well as localized cancer. Its major drawback, however, is that agents effective in killing neoplastic cells usually also have detrimental effects on normal cells, particularly the rapidly proliferating ones of the gastrointestinal tract and bone marrow, and cancer chemotherapy is ultimately limited by the toxicity of the drugs to these normal tissues, especially when employed in high dosages. One possible approach aimed at overcoming these limitations is the attaching of chemotherapeutic drugs to high molecular weight carriers. As a result of the macromolecularization of the drug, its activity might disappear. On the other hand, if the resulting conjugate still possesses drug activity, it will differ in some respects from the low molecular weight substance. Macromolecular conjugates of anti-tumor drugs could affect their distribution in the body, and facilitate slow and continuous release, while providing greater stability of the active substances. This attachment could thus decrease the overall toxic effects of these compounds without reducing their profitable activity. This approach has been demonstrated with some anti-cancer drugs (e.g., Szekerke et al. 1972a, Chu & Whiteley 1977, Bernstein et al. 1978). The ideal carrier for increasing the effectiveness of anti-tumor drugs would be the one that could recognize the target cell so as to selectively increase the local concentration of the drug, thus performing site-directed killing of the tumor cell.

The Use of Cyclosporin A Immunosuppression in Organ Grafting

Abstract: Since the first human kidney allografts were performed by Hume (Hume et al. ] 952). a wide search has been made for ways to control the immune response to protect foreign grafts from rejection. With the advent of Azathioprine (Calne 1961) and its subsequent combination with steroids (Starzl et al. 1963) kidney transplantation has become a viable and economically attractive therapy for renal failure. While the results achieved with Azathioprine and steroids are, in practice, far better than could reasonably be expected on theoretical grounds, rejection still remains the greatest single cause of graft loss, with half of the transplanted kidneys failing within I year (Human Renal Transplant Registry 1977). Furthermore, those patients with successful grafts often suffer severely from the side-effects of the immunosuppressive regime (Calne 1979). Thus there is a real need for a safer, more efficient means of controlling the immune system. In the years since the advent of Azathioprine, there have been very few clinically applicable advances in this field. One of these few is the recent introduction of an entirely new immunosuppressive drug called Cyclosporin A.

Neoplastic B cells as targets for antibody-ricin A chain immunotoxins.

Abstract: The targeting of toxic agents to tumor cells in vivo has been a goal of immunological research since the studies of Ehrlich (Himmelweit 1960). Successful application of this technique requires tumor-specific antibody whose activity remains unaltered following its covalent conjugation to a toxic agent. Moreover, the toxic portion of the conjugate should remain inactive until bound to the tumor cell via its antibody portion. In the studies described in this review, we have used an antibody against the cell surface immunoglobulin idiotype (Id) of a B cell tumor as our model system. B cell tumors are virtually always monoclonal in origin; hence each tumor cell that bears surface immunoglobulin expresses a particular Id (Fu et al. 1975. Schroer et al. 1974, Salsano et al. 1974). Since the Id is present on only a very small number of normal B cells (approximately l/lO*), the Id is operationally a tumor-specific antigen. Other advantages of using B cell tumors as model systems for antibody targeting studies include the availability of antibodies against other determinants on the cell surface immunoglobulin molecule (isotype, allotype, etc.) and a large body of information concerning the role of particular organs (e.g., spleen), cell types (T cells, macrophages) and lymphokines on the replication and differentiation of both normal and neoplastic B cells. In addition, a large number of humans with B cell tumors do not respond well to conventional chemo/radiotherapy (Lennert & Mohri 1978) and there is, therefore, a need to improve treatment. Recent studies utihzing antibody-directed targeting of toxic peptides to the surface of neoplastic cells are summarized in Table I and are reviewed in this volume. In general, the results of these studies have been promising. However,