Showing papers on "Immune system published in 1975"

"Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype.

Abstract: In the spleens of young, adult mice there exist naturally occurring killer lymphocytes with specificity for mouse Moloney leukemia cells. The lytic activity was directed against syngeneic or allogeneic Moloney leukemia cells to a similar extent, but was primarily expressed when tested against in vitro grown leukemia cells. Two leukemias of non-Moloney origin were resistant and so was the mastocytoma line P815. Although killer activity varied between different strains of mice, the specificity of lysis was the same as indicated by competition experiments using unlabeled Moloney or other tumor cells as inhibitors in the cytotoxic assays. Capacity to compete and sensitivy to lysis by the killer cells were found to be highly positively correlated. Analysis of the kinetics of the cytotoxic assay revealed a rapid induction of lysis within one to four hours, arguing against any conventional in vitro induction of immune response. No evidence was found of soluble factors playing any role in the cytolytic assay.

Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis.

Abstract: Human peripheral blood polymorphonuclear leukocytes, when exposed to appropriate stimuli, generate significant amounts of superoxide anion (O-.2), a highly reactive molecule which is possibly involved in bacterial killing. Since the subcellular localization and mechanism of activation of O-.2 generating systems are unknown, we have investigated superoxide dismutase-inhibitable cytochrome c reduction (attributable to O-.2) by, and lysosomal enzyme release from, normal polymorphonuclear leukocytes and cells rendered incapable of ingesting particles by treatment with cytochalasin B. Neither phagocytosis nor lysosomal degranulation were prerequisites for enhanced O-.2 generation. Cytochalasin B-treated cells exposed to (a) serum-treated zymosan, a C3b receptor stimulus; (b) heat aggregated human IgG, an Fc receptor stimulus; and (c) the complement component, C5a, generated enhanced amounts of O-.2 in a time and concentration-dependent fashion. These cells also responded by releasing lysosomal enzymes, but there was no correlation between the ability of any immune reactant to provoke enzyme release and its ability to stimulate O-.2 generation. The three stimuli also enhanced O-.2 generation by normal (untreated) polymorphonuclear leukocytes, but only serum-treated zymosan and aggregated IgG were capable of provoking lysosomal enzyme release from normal cells. Untreated zymosan and native IgG neither stimulated O-.2 production nor provoked lysomal enzyme release. Since enhanced O-.2 production was stimulated by immune reactants in the absence of phagocytosis, the O-.2 generating system is very likely associated with the external plasma membrane of the polymorphonuclear leukocyte. Leukocyte membrane receptors for complement and immunoglobulins may therefore not only serve in particle recognition but also may initiate biochemical events which accompany phagocytosis and killing.

H-2 compatability requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D;.

Abstract: Use of syngeneic, allogeneic, F1, AND H-2 recombinatn mice has shown that animals injected with lymphocytic choriomeningitis (LCM) virus generate T cells which are cytotoxic for H-2K or H-2D compatible, but not H-2 different, virus-infected target cells. Three separate lines of evidence are presented which indicate that these immune T cells are sensitized to "altered-self," the self antigens involved being coded for in the H-2K or H-2d regions. Firstly, cytotoxic activity associated with mutuality at H-2D iy, lysis mediated by immune T cells from F1 or H-2 recombinant mice is specifically inhibited only by presence of unlabeled, virus-infected cells that are H-2 compatible with the targets. Thirdly, LCM-immune F1 and H-2 recombinant T cells inoculated into irradiated, virus-infected recipients proliferate only to kill target cells that are H-2 compatible with both the donor and the recipient. All of these experiments establish that there is a dissociation of T-cell activities between parental haplotypes in F1 mice, and between H-2K and H-2D in recombinants. It would thus seem that there are at least two specificities of tlcm-immune T cells in homozygotes, associated with either H-2K or H-2D, and four specificities in F1 hybrids. The significance of these findings, with respect both to gene duplication and to the marked polymorphism in the H-2 system, is discussed.

A new analysis of allogeneic interactions.

Abstract: Allogeneic reactions have conventionally been considered as typical immune responses by one population of cells to antigens present on the other. This view is inadequate, since it does not explain many features of these reactions, among which are: (1) reactivity is much higher between different strains within a species than between species, in spite of the much greater antigenic disparity in the second case; (2) a very high proportion of cells may respond to allogeneic stimuli; (3) major histocompatibility differences are not essential for vigorous allogeneic reactions; (4) the responding population need not be immunologically competent to respond to antigens of the stimulating population; (5) the stimulating population must be both metabolically active and immunocompetent. We have tried to produce a model of cell interaction which will account for these and other anomalies, which at the same time explaining both normal antigenic stimulation (through cell-cell cooperation) and allogeneic interactions as examples of the same basic mechanisms. The model is based on the Bretscher-Cohn scheme of cell interaction. An allogeneic reaction is seen as having two stages: (1) Cells come together when antibody receptors on cells of one population combine with antigens on cells of the other. To this extent, our model is the same as the conventional one. It need not be the responding population which has the receptors, however. (2) A species-specific proliferation signal passes between the cells. This is the same signal as is involved in normal antibody induction. Even antigen-receptor bonds which are very weak may result in effective stimulation of one or both partners because of enhancing effect of this signal, and because the antigens involved are probably repeated over the cell surface, enabling multipoint binding. This explains the very proportions of cells which proliferate. The exact outcome of any allogeneic interaction will depend on which of the two populations have antibody receptors for antigens on the other, which can produce the proliferative stimulus, and which can respond to either the proliferative signal alone or to this stimulus plus antigen.

In vitro cell-mediated immune responses to the male specific(H-Y) antigen in mice.

Abstract: C57BL/10 female mice were primed to the male specific antigen H-Y, either by grafting with syngeneic male tail skin or by ip injection of syngeneic male spleen cells Primed female spleen cells, either unseparated or filtered through nylon wool to remove most of the B lymphocytes, were then cultured for 5 days in vitro with irradiated syngeneic male spleen cells and assayed against 51Cr-labeled target cells Both unseparated and nylon wool filtered female cells displayed significant cytotoxic activity restricted to male target cells Pretreatment of sensitized female cells with antitheta serum and complement just before assay abolished cytotoxic responses We were unable to demonstrate cell-mediated cytotoxic responses into two nonresponding strains, CBA and B10A, which fail to reject male isografts The cytotoxic activity of C57BL/10 female cells was restricted to male target cells histocompatible with C57BL/10 over at least a portion of the major (H-2) histocompatibility complex We conclude that secondary in vitro cytotoxic responses against the H-Y antigen are mediated by cytotoxic T lymphocytes, and that the H-Y target cell antigen may be specified by the H-2 complex

Reticulum cell sarcoma: an effector cell in antibody-dependent cell-mediated immunity.

Abstract: A transplantable, murine reticulum cell sarcoma is described which exhibits the cytologic, adherence, and phagocytic properties of macrophages. It forms specific rosettes with erythrocytes in the presence of the corresponding anti-serum. The ascites cells mediate antibody-dependent cellular immunity as assayed by release of radioactivity from 51Cr-labeled erythrocytes. The contribution of contaminating host cells in the cytotoxic reaction was ruled out by growing the tumor in F1 mice and removing the host cells by anti-H2 serum and complement. The tumor cells have receptors for IgG2a and IgG2b immunoglobulins. The availability of a pure population of effector cells in the immune system allows study of the biochemical processes pursuant to lysis of foreign cells.

H-2 compatibility is required for t-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus

Abstract: Maximal cell-mediated lysis of targets infected with lymphocytic choriomeningitis virus occurs only within a H-2 compatible system. Syngeneic immune spleen cells are at least 100 times as effective as are allogeneic lymphocytes. Reciprocal restriction of cytotoxic T-cell activity has been shown to operative between H-2k, H-2d, and H-2b. Experiments with cogenic mice have localized the effect to the H-2 gene complex. Furthermore, the observation that lymphocytes from H-2a mice cause high specific 51Cr release from either H-2d virus-infected cells, indicates that identity at either the K or the D end of the H-2 gene complex is sufficient for this lytic interaction.

Genetics of natural resistance to herpesvirus infections in mice.

Abstract: INHERITED resistance to virus infections has been demonstrated in several murine systems1–6. Susceptibility to mouse hepatitis virus3 and resistance to arbovirus7 infections in mice are dominant traits associated with the capacity of macrophages from the susceptible strains to replicate virus. Resistance to Friend leukaemia virus- and Gross leukaemia virus-induced leukaemogenesis is determined by at least two genes, one closely linked to the immune response genes of the mouse8. Conversely, susceptibility to lymphocytic choriomeningitis (LCM) virus infections in mice has been associated with a gene closely linked to the immune response genes9. The latter seems to be associated with the cell-mediated immune response to LCM which causes tissue damage and leads to death. Cell-mediated immunity seems to be important in resistance against herpes simplex virus (HSV) infections10–12. Analysis of the aspects of cell-mediated immunity which might be involved in resistance in man is complicated by the uncontrollable factors associated with activation of latent herpesvirus infections. I have developed a mouse model which has shown that at least three genes are responsible for resistance to HSV. Although preliminary evidence suggests that resistance is immunologically mediated, resistance genes do not seem to be closely linked to the histocompatibility region of the mouse.

Subversion of immune system by tumor cells and role of prostaglandins

Abstract: Mice bearing syngeneic tumors, chemical and virus-induced, became immunologically unresponsive to sheep erythrocytes. The increase in the degree of unresponsiveness with tumor growth suggested a causal relationship. Immunosuppression was in fact caused by the tumor cells because the addition of tumor cells to in vitro cultures of spleen cells and sheep erythrocytes resulted in suppression of antibody response. Suppression was dose dependent with a ratio of 1 to 1000 of tumor cells to spleen cells sufficient to produce significant suppression. Prostaglandins were found to have a role in immunosuppression by tumor cells in that PGE2 was itself immunosuppressive and in that indomethacin and aspirin, inhibitors of prostaglandin synthetases, blocked immunosuppression in vitro and retarded tumor growth in vivo. These findings suggest that tumors, although antigenic, may be able to escape immuno-sureillance by their host by means of subverting the immune system. Thus, success of immunotherapy may well depend on our ability to prevent or block the immunosuppressive activity of tumors.

Changes in blood hormone levels during the immune response.

Abstract: Injection of three different antigens into rats or mice led in the course of several days to about a threefold increase in serum corticosterone levels and concommitantly to a decrease in thyroxine (rats). In view of the known immuno-suppressive effect of the glucocorticoids the possibility is considered that the endocrine changes induced during the immune response could significantly modulate the subsequent character of the immune response, e.i. magnitude, duration and lymphoid cell proliferation, however, a more complete pattern of hormonal variations and their cause needs to be established. These findings while admittedly preliminary, suffice to provide an indication of a temporal pattern of hormonal change during the immune response which could be important in immunoregulation.

Lymphocyte migration and immune responses.

Abstract: Vol. 7: XII + 334 p., 46 fig., 42 tab., 1963. ISBN 3-8055-1105-1 Vol. 8: X + 261 p., 35 fig., 32 tab., 1964. ISBN 3-8055-1107-8 Vol. 9: VIII + 308 p., 45 fig., 9 tab., 1965. ISBN 3-8055-0373-3 Vol. 10: XII + 292 p., 16 fig., 14 tab., 1967. ISBN 3-8055-0374-1 Vol. 11: XX + 184 p., 40 fig., 21 tab., 1967. ISBN 3-8055-0376-8 Vol. 12: XIV + 317 p., 27 fig., 12 tab., 1968. ISBN 3-8055-0377-6 Vol. 13: XXII + 429 p., 51 fig., 16 tab., 1969. ISBN 3-8055-0378-4 Vol. 14: XVI + 340 p., 35 fig., 18 tab., 1970. ISBN 3-8055-0379-2 Vol. 15: XVI + 485 p., 31 fig., 41 tab., 1971. ISBN 3-8055-1238-4 Vol. 16: XII + 498 p., 52 fig., 31 tab., 2 cpl., 1972. ISBN 3-8055-1335-6 Vol. 17: IX + 299 p., 29 fig., 30 tab., 1973. ISBN 3-8055-1539-1 Vol. 18: XII + 477 p., 46 fig., 38 tab., 1975. ISBN 3-8055-1660-6

Phagocytosis and cytolysis by a macrophage tumour and its cloned cell line.

Abstract: MACROPHAGES found in lymphoid and other tissues are defined by adherence, staining, morphology and rapid pinocytosis. Subtypes of macrophage-like cells have been distinguished on the basis of density and functional properties1–3. Immune macrophages4 and normal macrophages in the presence of specific antiserum5–8 will lyse relevant target cells, and can phagocytose cells by an independent mechanism9–12, but it has not been shown that the same cell type can carry out both functions.

Evidence for the clonal abortion theory of B-lymphocyte tolerance.

Abstract: This paper deals with the behavior of adult mouse bone marrow cells placed in tissue culture with or without antigen, and subsequently assessed for immune competence after adoptive transfer into lethally X-irradiated, syngeneic hosts. Attention was focussed on B lymphocytes through using hapten human gamma globulin (HGG) preparations as putative tolerogens in tissue culture, the T-cell-independent antigens DNP-POL and NIP-POL as challenge injections in adoptive hosts, and numbers of hapten-specific PFC in host spleens for the quantitation of immune competence. It was found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. Dose-response studies showed the lowest effective antigen concentration to be between 2.5 times 10- minus 10 and 2.5 times 10- minus 9 M, and a standard concentration of 2.5 times 10- minus 8 M was chosen as producing near maximal effects. The tolerance was antigen-specific and time-dependent, being maximal only when antigen was present continuously as the cultured cells was maturing. It did not depend on the presence of T lymphocytes in marrow, and was not of an "infectious" type. In contrast to tolerogenesis of mature B lymphocytes by high antigen concentrations, it could not be abolished by lipopolysaccharide. We speculate that clonal abortion may be a tolerance mechanism of great physiological significance for self-recognition, and discuss the results in the framework of other recent tolerance models, including those involving receptor blockade and suppressor T cells.

A disquisition on suppressor T cells.

Abstract: The main points that I have put forth are that: (1) suppressor T cell activity cannot be explained as simply being too much help; (2) feedback signals from target cells are of crucial importance in determining and maintaining the activity of suppressor T cells; (3) whenever T cells are triggered by antigen, suppression occurs. Immune responses only occur when countermanding signals are also generated. Both intrinsic and extrinsic adjuvanticity is the operational production of countermanding signals; (4) memory T cells are qualitatively different from normal T cells in their sensitivity to feedback signals and also in their susceptibility to suppression; (5) mature thymus dependent B cells cannot be rendered tolerant by the direct action of antigen, while immature and thymus independent B cells can; (6) the mechanism of suppression induced by exogenously administered antigens and that by normal differentiation products (i.e.: GVH; allotypes), is different; (7) generation of suppressor cells requires or results from complex interactions between subpopulations of cells, making it impossible under present conditions to determine which cell is doing what and to which; (8) further work is required before a full understanding of the importance, mechanism of action and other aspects of suppressor T cell function can be fully understood.

Immune exclusion is a function of IgA.

Abstract: PREVENTION of entry of antigen into the systemic circulation through mucous membranes depends partly on the physical integrity of the mucous membranes and the mucous layer and, no doubt, on other nonspecific mechanisms. These systems are, however, not completely effective and there is also a specific acquired capacity for immune exclusion of antigen. For example, everted gut sacs from rats previously fed with an antigen show specific reduced transmission of the antigen, as compared with sacs prepared from animals not fed in this way1. Passive transfer in vivo, using cell free homogenates of mucosae from antigen-fed animals has also been reported but the mechanism was not identified2. One possibility is IgA antibody, the principal immunoglobulin of mucous secretions3, and this is supported by the demonstration of circulating antibody to food proteins in IgA deficient subjects4, and the association of allergic disease with IgA deficiency, either permanent5 or transient6.

Expression of T-cell differentiation antigens on effector cells in cell-mediated cytotoxicity in vitro. Evidence for functional heterogeneity related to the surface phenotype of T cells.

Abstract: The cell-mediated cytotoxicity (CMC) of nonadherent cells from the peritoneal cavity (NAPC) of alloimmunized mice can be measured by the [3H]proline microassay. The exhibition of thymus-derived (T) cell antigens on these killer cells was studied by incubating them with the relevant T-cell antisera and complement (C), under optimal conditions for lysis, before performance of the CMC assay. Under these conditions, the following T-cell antigens were demonstrable on the killer population in terms of percent reduction in CMC by the respective antisera: (a) Thy-1.1 (83%) and Thy-1.2 (100%), (b) MSLA (86%), (c) NTA-RA (a T-cell antigen recognized by naturally occurring autoantibody of NZB mice) (62%), (d) Ly1.1 )58%, (e) Ly-2.1 (11%; considered a marginal result) and Ly-2.2 (63%), and (f) Ly-3.2 (77%). The following were not demonstrable: (g) TL, and (h) Ly-1.2. (i) The antigen Ly-3.1 was not studied. Omission of C deprived all T-cell antisera tested of their capacity to suppress CMC, indicating that the cell components recognized by such antisera may perform no direct function in CMC. On the assumption that all Ly+ cells are Thy-1+, it is clear that the T-cell members of the immune NAPC population must be heterogenous. This follows from the fact that the proportions of T cells lysed by different Ly antisera did not correspond with ensuing degree of loss of CMC capacity. The extremes were represented by anti-Ly-1.2 (74% Thy-1+ cells lysed, but no reduction in CMC) and Ly-3.2 (54% Thy-1+ cells lysed, with 77% reduction in CMC). From this initial survey it appears that the C57BL/6 mice killer T-cell population active in CMC in vitro is relatively rich in surface antigens of the Ly-2/Ly-3 category and relatively poor in representation of the Ly-1 surface antigens. It remains to be seen whether this killer cell phenotype, poor in Ly-1 and rich in Ly-2/Ly-3, is characteristic of the mouse generally. From these results it appears that subsets of T cells with different immunological functions may exhibit qualitative or quantitative differences in surface antigens specified by different Ly loci; this will be easier to assess in the future when the results of experiments with the same Ly antisera but dealing with T-cell functions other than CMC become available.

Hodgkin's disease. An immunodepleting and immunosuppressive disorder.

Abstract: Irradiated leukocytes or mononuclear leukocytes, from 16 out of 30 patients with Hodgkin's disease and from one patient with the Sezary syndrome, stimulated in culture subnormal (3H)thymidine incorporation by allogeneic lymphocytes from normal individuals. This abnormality was not demonstrated in any of 30 other patients with non-Hodgkin's lymphomas. Subnormal mixed leukocyte culture reaction activation was caused by suppression of the mixed leukocyte reaction by patients' cells. Inhibition of the reaction by patient mononuclear leukocytes was corrected when adherent cells were removed or when protein synthesis was inhibited with cycloheximide. The inhibitory cells were probably lymphocytes since selective removal of phagocytic cells did not remove the inhibition by other patient mononuclear leukocytes. The presence in culture of as few as 2,500 granulocytes per mm3 also reduced responses when target cells were from patients with Hodgkin's disease. Patient cells no longer suppressed the mixed leukocyte reaction after patients entered clinical remission which suggests that suppression is a reversible, disease-related abnormality. Thus, the immune deficiency with advance Hodgkin's disease caused by ly lymphocyte depletion may be compounded by a relative excess of suppressor lymphocytes. The overall immunodeficiency may be further compounded by suppression of immune response by granulocytes at even physiologic concentrations.

X-linked B-lymphocyte immune defect in CBA/N mice. II. Studies of the mechanisms underlying the immune defect.

Abstract: The mechanisms underlying the X-linked thymus-independent (B) lymphocyte functional defect in the CBA/N (CN) mice and their F1 progeny were studied. Immune defective mice were unable to respond to the T-independent antigen 2,4-dinitrophenyl-lysyl-derivative of Ficoll (DNP-lys-Ficoll) but were able to form antibody against the highly cross-reactive hapten (trinitrophenyl) when it was coupled to an erythrocyte carrier. Immune defective CN X DBA/2N (DN) F1 male mice, which do not normally respond to T-independent antigens, were able to respond to both polyribosinic-polyribocytidylic acid and DNP-lys-Ficoll after the administration of CN X DN F1 female spleen cells even if these cells had been depleted of T lymphocytes. In addition, it was shown that the inability of the CN mice and their F1 progeny to respond to T-independent antigens was not due to an intrinsic abnormality of their microenvironment or the suppressive actions of a T lymphocyte. Our data present evidence that the X-linked defect in the CN mice is due to an intrinsic defect in B-lymphocyte development.

The modulation of lymphocyte functions by molecules secreted by macrophages. I. Description and partial biochemical analysis.

Abstract: Culture fluids of peritoneal exudate cells rich in macrophages stimulated DNA synthesis of thymocytes and, to lesser extent, of spleen cells. We also investigated the effects of culture fluids from macrophages on the in vitro response to a hapten-carrier protein (fluorescein-menocyanin) using spleen cells from immune mice. Macrophage culture fluids contained an activity that increased the plaque-forming cell response of both IgG and IgM class. This increase was observed in the absence of any added hapten protein to the culture. The helper function of T lymphocytes (as evidenced by challenging with the hapten on the homologous carrier) was also increased by the macrophage culture fluid. However, this enhancement was best observed in conditions of relatively low T-cell activity. Also, the macrophage fluid allowed spleen cells of nude athymic mice to make a plaque-forming cell response to sheep red blood cells of both the IgM and IgG class. The macrophage was the cell source of the stimulatory molecule since it was generated only in cultures of macrophages devoid of significant number of lymphocytes. Stimulatory activity was not found in cultures of lymphocytes, mouse embryo cells, or 3T3 cells. The thymocyte stimulatory molecule did not contain H-2 antigens, was resistant to diisopropylfluorophosphate treatment, eluted from Sephadex with a size ranging from 15,000 to 21,000 daltons, and was sensitive to chymotrypsin and pepsin.

X-linked B-lymphocyte immune defect in CBA/HN mice. I. Studies of the function and composition of spleen cells.

Abstract: A study of the composition and functional properties of spleen cells from the immune deficient CBA/HN mice and their F1 progeny is reported. While abnormalities were seen in both the numbers and function of thymus-independent (B) lymphocytes, all studies involving thymus-dependent (T) lymphocytes were normal. The X-linked nature of the immune defect in these mice was therefore attributed to abnormal or absent B lymphocytes. The possible nature of this defect and the similarity of the immune defect in these mice to certain human X-linked immunodeficiency diseases are discussed.

A mechanism for the induction of immunological tolerance by antigen feeding: antigen-antibody complexes.

Abstract: We have previously reported on the induction, in mice, of a systemic (splenic) immune response with IgA as the dominant antibody, as a result of a short (4 day) intragastric immunization course with foreign erythrocytes This response was followed by a prolonged period of hyporesponsiveness to similarly administered antigen Here it is shown that this hyporesponsiveness is also manifested towards antigen given intraperitoneally, and that one is therefore dealing with tolerance, not with failure to absorb antigen from the gut In contrast, mice primed parenterally and then challenged intragastrically behaved as if never having any previous contact with the antigen, ie, with a primary-type splenic response of predominant IgA character This agrees with our former conclusion that splenic responses to enterically absorbed antigen reflect colonization of the spleen by cells sensitized locally in the gut wall, a site not readily primed by the parenteral route Serum from intragastrically immunized mice contained a very active tolerogen In vivo, it was capable of conferring tolerance to nonimmune recipient mice In vitro, it paralyzed the activity of antibody-producing cells Inhibitory sera has weak antibody activity, restricted to the IgA class, and contained immune complexes reacting with rheumatoid factor but not with C1q Elimination of these complexes by means by insolubilized rheumatoid factor abolished the tolerogenic effect In conclusion, the enterically induced tolerogen seems to consist of immune complexes with IgA as the antibody

The role of products of the histocompatibility gene complex in immune responses

Abstract: The data of our most recent investigations have mapped the relevant gene or genes coding for CI molecules to the I region of the H-2 complex of the mouse. Thus, T and B lymphocytes from donor mice which differ at genes in either the K , S or D regions of H-2 (or combinations of the latter), but which are identical for genes in the I region, are capable of developing cooperative immune responses. Conversely, gene differences in the I region, more precisely in the Ir-1A and Ir-1B subregions, prevent the development of T-B cell interactions irrespective of the existence of gene identities elsewhere in the H-2 complex (including the I-C subregion).

Receptors for immunoglobulin and complement on human alveolar macrophages.

Abstract: Specific cell membrane surface receptors for immunoglobulin and complement components were identified by rosette fromation on in vitro cultured alveolar macrophages obtained from 24 humans and from rabbits. Respiratory macrophages have easily identified receptors for IgG and the C3b fragment of the third component of complement. A macrophage receptor for the C3d fragment was detected only when purified human complement components were used to form erythrocyte-antibody-C3 immune complexes but was not detected when whole human serum was used as the source of complement. No IgM cell receptor was identified. Thus, with respect to membrane receptors, alveolar macrophages resemble peripheral blood monocytes. These studies in addition emphasize the importance of using a variety of immune reagents, expecially the use of human reagents, to determine correctly these cell receptors.

Host Defenses Against Influenza Virus: The Role of Anti-Hemagglutinin Antibody

Abstract: In CBA mice the protection provided by transferred immune spleen cells or by antibody has been investigated in immunologically intact, cyclophosphamide-treated and thymus-deprived animals infected with A/PR8 virus. The degree of protection was more closely related to serum antibody levels than to the presence of immune lymphocytes in recipients. Comparison of the protective efficiency of various anti-influenza antisera with different specificities within an influenza A subtype indicated that antibodies recognizing the strain-specific determinants of the influenza hemagglutinin have an important role in protection. Physiologic amounts of transferred antibodies were shown to protect immunodepressed mice, suggesting that, provided a sufficient amount of specific antibodies is secreted, the participation of effectors of cell-mediated immunity is not essential. However, our results suggest that thymus-derived lymphocytes have an indirect role in protection by enhancing, through their helper effect, the secretion of anti-influenza antibodies.

Macrophage-lymphocyte interaction. II. Antigen-mediated physical interactions between immune guinea pig lymph node lymphocytes and syngeneic macrophages.

Abstract: The effect of specific antigen on the development of physical interactions between lymph node lymphocytes (LNL) obtained from animals which had been immunized to that antigen and macrophages was examined. We found that the presence of antigen, either limited to the macrophage () or free in the medium, profoundly increased the degree of ) or free in the medium, profoundly increased the degree of Mphi-LNL interaction observed. This enhanced interaction was dependent on the coincidence in the cultures of Mphi bearing antigen and LNL from animals specifically immunized to that antigen. Although antigen-independent interactions developed equally well between syngeneic and allogeneic combinations of lymphocytes and macrophages, antigen mediated interactions required that macrophages and lymphocytes be syngeneic. Prolongation of antigen-mediated Mphi-LNL interactions resulted in the induction of LNL DNA synthesis, initially involving those lymphocytes physically associated with antigen-bearing Mphi. These studies are interpreted to indicate that physical interaction between immune lymphocytes and antigen-bearing Mphi represents a morphological correlate of the functional activation of immune lymphocytes. Further, it is suggested that the physical events involved in lymphocyte proliferation may proceed sequentially from antigen-independent reversible binding of lymphocytes by macrophages to prolonged antigen-stabilized interaction eventuating in the triggering of specifically immune lymphocytes.

A role for the eosinophil in acquired resistance to Schistosoma mansoni infection as determined by antieosinophil serum.

Abstract: Partial immunity to schistosomiasis mansoni has been demonstrated in mice and has recently been transferred passively with serum, but not with cells. In vitro studies using human and rodent materials have demonstrated antibody-dependent cell-mediated damage to immature schistosomes (schistosomula); the cell involved in some of these in vitro systems appears to be the neutrophil and in others the eosinophil is suspected. In the present study the effect of antileukocyte sera on partial immunity to schistosomiasis was tested in vivo using quantitative assay systems for schistosomula in the lungs and adult worms in the portal venous system. Mice infected with 10 cercariae of Schistosoma mansoni 16 and 32 wk before challenge with 500 cercariae showed reductions in the recovery of schistosomula at 4 and 6 days of approximately 40%; adult worm recovery was reduced by 60%. Treatment with antilymphocyte, antimacrophage, or antineutrophil serum had no effect on the numbers of schistosomula recovered from the lungs of immune animals, but in the mice treated with antieosinophil serum the numbers of schistosomula and adult worms recovered increased to the levels seen in normal nonimmune animals. Furthermore, sera collected from the partially immune mice and passively transferred to uninfected mice conferred a marked resistance to infection as measured by recovery of schistosomula; this was also abrogated by treatment with antieosinophil serum. These studies suggest that antibody-dependent cell-mediated immunity to schistosomiasis occurs in vivo, and also establishes a role for the eosinophil in immune systems.

Requirement for vasoactive amines for production of delayed-type hypersensitvity skin reactions.

Abstract: The skin sites of the mouse where delayed-type hypersensitivity (DTH) reactions are most easily elicited (foot pads and ears) are particularly rich in 5-hydroxytryptamine (5-HT)-containing mast cells. Since mice are deficient in circulating basophils, which play a role in at least some DTH reactions, we investigated the possibility that the mast cells were playing an important role in the evolution of the skin reactions of DTH in mice. We found that reserpine, a drug which depletes mast cells of 5-HT, abolished the ability of the mouse to make DTH reactions in the skin. The suppressive effect of reserpine could be partially blocked by monoamine oxidase inhibitors which prevent the degradation of 5-HT in the cytosol of the mast cell. Spleen cells of immune, reserpine-treated mice transferred DTH reactions to nonimmune mice normally, indicating that the reserpine treatment did not affect immune T cells. DTH reactions could not be transferred into reserpine-treated mice. We suggest that T cells are continually emigrating from the blood, through postcapillary venule endothelium, by a mechanism which does not depend on vasoactive amines. If they are appropriately immune and meet the homologous antigen in the tissue, they induce mast cells to release vasoactive amines which cause postcapillary venule endothelial cells to separate, allowing the egress from the blood of cells which ordinarily do not recirculate. The secondarily arriving vasoactive amine-dependent cells are responsible for the micro- and macroscopic lesions of DTH reactions. Chemotactic factors may also be involved in bringing cells to the DTH reaction sites but we propose that T-cell regulation of vasoactive amine-containing cells allows the effector cells to pass through the endothelial gates after they are called.

Comparative mapping of the local distribution of immunoglobulin-containing cells in ulcerative colitis and Crohn's disease of the colon.

Abstract: The local response pattern of immunoglobulin-containing cells was compared in Crohn's disease and ulcerative colitis by paired immunohistochemistry on specimens of the large bowel wall. In the "Crohn mucosa" with persisting glands the total cell count was on the average raised more than three times compared with controls. The numbers of IgA, IgM and IgG immunocytes were increased 2.0, 4.8 and 28.6 times, respectively. Only 0-2 IgD- and IgE-containing cells were generally found per section. No consistent differences in the mucosal response pattern were revealed when Crohn's disease was compared with ulcerative colitis. The deeper layers of the bowel wall were in both diseases more or less densely infiltrated by immunocytes-IgG cells compromising about 80%. Immunoglobulin-containing cells in the muscularis propria and subserosa were characteristically found in Crohn's disease. There was no indication of a primary defect in the secretory immunoglobulin system which appeared to be normal in areas with intact glands. The pronounced local humoral immune response, particularly that involving IgG, might be of pathogenetic importance by aggravating and perpetuating in the inflammatory bowel disease.

Thymic involution: effect on T cell differentiation.

Abstract: The thymus of long-lived BC3F mice involutes progressively throughout life, beginning at 6 weeks of age. This is manifested by the loss of cortical lymphoid mass and by the degenerative changes in epithelial cells. The purpose of this study was to determine to what extent age-related degenerative changes of the thymus affect its capacity to influence the maturation of thymic-derived (T) cells. Accordingly, thymic lobes of mice ranging in age from 1 day to 33 months were implanted under the kidney capsule of T cell-deprived syngeneic young adult TXB mice, and the emergence of T cells was assessed kinetically by various morphologic and functional indices which may be reflective of different T cell subpopulations. They are: a) histology of the thymsu graft, b) lymphocyte repopulation of the T cell-dependent areas of lymph nodes, c) total number of splenic lymphocytes carrying theta antigens (theta-+), d) T cell-dependent humoral immune response and e) proliferative response of splenic cells to plant lectins, phytohemagglutinin (PHA) and succinyl-concanavalin A (s-Con A), and allogeneic lymphocytes. The results revealed that the T cell-transforming influence of thymic tissues generally decreases with increasing age. The difference in the patterns of recovery of the various indices of thymus-grafted TXB mice suggests that the extent to which T cells can mature is dependent upon the degree of involution the thymic tissue has undergone with age. In particular thymic tissues lose the capacity to influence the following functions with advancing age: 1) lymphocyte repopulation of the T cell-dependent areas of lymph nodes; 2) mitogenic reactivity of splenic cells to T cell-specific mitogens (PHA and s-Con A): 3) number of splenic theta-+ lymphocytes and splenic T cell helper function; and 4) mitogenic reactivity of splenic T cells to allogeneic lymphocytes.