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Factors influencing the immune enhancement of intrapulmonary bactericidal mechanisms.

The effect of specific immunization on the antibacterial defense mechanisms of the murine lung was assessed against Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus aureus (Smith), Serratia marcescens, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. Immunization by aerosol inhalation significantly enhanced the intrapulmonary killing of Pseudomonas aeruginosa and Proteus mirabilis but not the remaining organisms. With P. mirabilis, systemic immunization induced higher titers of specific serum agglutinins as compared with local respiratory tract immunization; however, local immunization was more effective in enhancing pulmonary bactericidal activity than was parenteral vaccination. Passive immunity against P. mirabilis or aerogenic challenge with preopsonized P. mirabilis significantly enhanced intrapulmonary killing of the homologous organism. With S. aureus, pulmonary bactericidal activity was not accelerated by aerosol challenge with the preopsonized organism, nor was it accelerated in passively immunized mice. These data demonstrate that the immune enhancement of pulmonary bactericidal activity is governed by the bacterium used for challenge and the route of immunization. The results further demonstrate that with P. mirabilis, antibody-mediated mechanisms are involved in the immune enhancement of pulmonary bactericidal activity.

Administration, Intranasal

Immunotherapy for cancer: an overview.

Immunotherapy of cancer is of interest to oncologists because it is specifically directed to cancer cells, sparing normal cells. While it is ineffective in most patients, especially those with widespread metastatic disease, it occasionally produces good results. Each of the available methods has inherent problems and, recently, attempts have been made to overcome some of these. There is a strong case for small-scale experimental trials in highly selected groups of patients who are intensively investigated for their immunologic status in relation to their tumour. Despite the lack of success in general, immunotherapy still appears to have a future as an adjunct to existing therapy in order to control as much as to cure residual tumour.

Adjuvants, Immunologic

Suppression of reaginic antibody formation. II. The use of adoptive transfer system for the study of immunological unresponsiveness.

By the use of the adoptive transfer system in syngeneic mice it was demonstrated that: i) spleen cells of animals tolerized by the i.v. injection of DNP8-MgammaG 1 month before adoptive transfer into x-irradiated recipients remained unresponsive when further challenged with the sensitizing antigen (DNP2.3-OA administered i.p. with Al (OH)3); by contrast, a significant response (typical of a secondary response) was obtained in recipients of cells from mice which had received only the sensitized antigen; ii) the anti-hapten IgE secondary response of primed cells was not affected by the presence of cells of tolerized mice when these two types of cells were administered and challenged together in x-irradiated recipients; iii) the transfer of spleen cells or serum of mice, tolerized 20 days before harvesting, into intact syngeneic recipients did not interfere with the normal development of the anti-DNP IgE response of the latter; iv) the anti-hapten responses of tolerized animals receiving spleen cells from normal or primed mice together with the sensitizing antigen resulted, respectively, in a primary or secondary response; (v) the unresponsive state of tolerized cells, achievkd by immunosuppression of the original donors with respect to the haptenic determinant, was maintained even after two serial exposures of the cells to the immunizing antigen in two consecutive adoptive cell transfers into x-irradiated recipients. These findings provide a strong basis for the interpretation that the hapten-specific tolerace induced in mice by treatment with DNP8-MphiG involved the elimination or inactivation of hapten-specific IgE-producing cells or the blockade of the receptors of these cells.

Animals

Induction of tolerance to nucleic acid determinants by administration of a complex of nucleoside D-glutamic acid and D-lysine (D-GL).

The administration of nucleosides coupled covalently to the copolymer of D-glutamic acid and D-lysine (D-GL) or to its stereoisomer, L-GL, induces a state of nucleoside (NUC)-specific tolerance in inbred SJL and BALB/c mice, irrespective of their immune status at the time of treatment. Such tolerance is characterized by the inability of treated animals to mount either primary or secondary, intact or adoptive, anti-NUC antibody responses following immunization with a highly immunogenic conjugate of NUC-Keyhole limpet hemocyanin. These observations have potential therapeutic importance in autoimmune processes involving anti-DNA antibody production.

Animals

Maturation of B lymphocytes in the rat. II. Subpopulations of virgin B lymphocytes in the spleen and thoracic duct lymph.

Thoracic duct and spleen cells of normal (unimmunized) adult rats were fractionated according to size by 1 times G velocity sedimentation. Fractions were tested for their ability to restore the adoptive antibody response of irradiated hosts to horse spleen ferritin. A constant source of T cells (small numbers of unfractionated thoracic duct cells) was added to each fraction in order to monitor the B cell activity of the latter. Although large and small cell fractions of the spleen showed restorative activity, only the small cell fractions of the thoracic duct lymph showed activity. The turnover rate of the spleen cell fractions was determined by treating donors with high specific-activity 3H-thymidine for 48 hr before splenectomy. Rapidly dividing cells are preferentially killed by this treatment. The results suggest that a considerable proportion of large, intermediate, and small virgin B cells turn over within 48 hr. The cell surface of the various spleen cell fractions was examined for the presence of immunoglobulin (Ig) and a receptor for complement. The percentage of Ig-bearing cells in the large cell fractions was similar to the percentage of cells bearing IgM and a receptor for complement. However, the majority of Ig-bearing cells in the small cell fractions did not show the latter two surface markers. Experiments with the fluorescence-activated cell sorter showed that the large functionally active B cells bore surface IgM. The experimental findings suggest that there are subpopulations of virgin B cells in the spleen of the adult rat which differ with respect to size, migration pattern, turnover rate, and cell surface characteristics. The relationship of these cells to one another is discussed in the framework of an antigen-independent model of B cell maturation in the rat.

Animals

Ontogeny of B-lymphocyte function with respect to the heterogeneity of antibody affinity-1,2.

Neonatal liver or adult spleen was used as a source of B-lymphocytes in reconstituting lethally irradiated, syngeneic mice. Recipients were all given excess adult, syngeneic thymus cells and were immunized with dinitrophenylated bovine gamma globulin. The distribution of avidities of plaque-forming cells produced by immunized recipients of neonatal liver was highly restricted in comparison with animals reconstituted with adult spleen indicating a restriction of B-lymphocyte heterogeneity in the neonatal mouse.

Animals

Adoptive transfer of experimental allergic encephalomyelitis (EAE): prevention of successful transfer by treatment of donors with myelin basic protein.

After onset of experimental allergic encephalomyelitis (EAE), guinea pigs can be effectively treated by injection with myelin basic protein (BP). In order to localize the site of action of BP, cells from sensitized donors treated with BP one, two, three, or four times after disease onset have been transferred to normal recipients. One injection of BP has no effect on ability of cells to transfer EAE. Two injections partially inhibit transfer. After the third and fourth injections the sensitized cells lose their capacity to transfer EAE. The therapeutic effect of BP previously demonstrated in actively sensitized guinea pigs must involve the specifically sensitized cells rather than the target organ.

Animals

Anti-receptor antibody. II. Induction of long-term unresponsiveness in neonatal mice.

We have examined the ability of anti-receptor antibody (ARA) to induce specific unresponsiveness to the hapten, phosphorylcholine (PC), in neonatal and adult mice. When ARA is given to adult mice, suppression is of short duration. Cells from such mice are responsive in vitro, indicating that suppression in vivo is probably due to blockade of receptors by persisting ARA. ARA given to neonatal mice induces long-term unresponsiveness. The mice apparently have decreased numbers of PC-responsive cells, since cells from such mice are unresponsive both in vitro and in adoptive transfer. Furthermore, cells from neonatally suppressed animals do not suppress the response of normal cells either in vitro or in adoptive transfer, indicating that unresponsiveness is most likely not due to active suppression. We therefore conclude that ARA given to neonates depletes the clone of receptor-bearing cells at the time ARA is given. Clonal depletion may result from antibody-dependent cell mediated cytotoxicity.

Animals

Studies on tolerance induction in vitro. I. Production of immunologically tolerant rabbit spleen cells and the transfer of tolerance to untreated cells.

Tolerance was induced in rabbit spleen cells by incubation with solubilized T2 phage (S-T2)2 at 37degrees C. Spleen cells thus treated maintained normal responsiveness to an unrelated antigen, S-SP82. Transfer of tolerance was demonstrated in in vitro in that the addition of washed tolerant cells caused suppression of the response of untreated cells to an immunogenic dose of S-T2. Evidence is presented that this suppression is not due to the transfer of tolerogenic quantities of antigen. Spleen cell populations depleted of adherent cells were still capable of being made tolerant and of transferring tolerance.

Animals

Effect of antiserum on transplantable hematopoietic colony-forming units during Rauscher leukemia development.

Studies have been carried out to determine the sensitivity of hematopoietic CFU-S from Rauscher leukemic mice to an antiserum against the disease prepared in syngeneic mice. Test of this antiserum against Rauscher virus prior to injection showed it to be effective both in vitro and in vivo. At the same time, normal serum was shown to be without effect either against the CFU-S or against the virus. Spleen CFU-S were obtained from control and leukemic mice over a sequence of days following Rauscher virus injection and assayed by transplantation technique. Prior to transplantation these were incubated in vitro in either normal syngeneic serum or syngeneic antiserum. Incubation with antiserum had no effect on CFU-S obtained from the spleens of normal mice. However, incubation in this antiserum of spleen CFU-S from Rauscher leukemic mice resulted in a reduction of up to 50% in their colony-forming ability. Additional tests with guinea pig complement suggested that the levels of inactivation seen are not complement limited. This antiserum-induced reduction in colony formation was first evident in the second week after the injection of virus, coincident with the onset of splenomegaly in the leukemic mice. Thereafter, sensitivity of CFU-S to the antiserlm could be detected up to the terminal point of the leukemia (44 days).

Animals

Immunotherapy of human acute leukaemia.

Conclusions are difficult to draw. In the six studies of immunotherapy of AML discussed, all the three employing BCG and cells showed a prolongation of survival and the major contributing factor to this prolongation of survival was extension of life after relapse. In the three studies using BCG alone only one shows a beneficial effect, but some more time must be allowed to elapse before this can be concluded with confidence.

Acute Disease

Evidence for specific suppression in the maintenance of immunologic tolerance.

Specific suppressor cells have been demonstrated in mice tolerant to the thymus-dependent antigen HGG. Transfer of normal thymocytes, normal spleen cells, or immune spleen cells into these tolerant mice did not restore immunocompetence to HGG. Furthermore, the transfer of tolerant spleen cells into normal recipients abrogated the response of these recipients to subsequent challenge with immunogenic HGG. Spleen cells removed from mice 5, 8, or 11 wk after the induction of tolerance specifically suppressed the response of normal spleen cells in an adoptive cell transfer system. The extent of suppression appears to be dependent upon how long after the induction of tolerance the cells were removed from the tolerant donors and how soon after transfer the recipients were challenged.

Animals

Inhibition by derivatives of phloretin of anaphylactic histamine release from human lung tissue and of prostaglandin F2alpha-induced bronchoconstriction.

Derivatives of phloretin (25-1,000 mug/ml) among them polyphloretin phosphate (PPP), inhibited in a dose-dependent manner anaphylactic (birch pollen or horse dander) histamine release from human lung tissue passively sensitized with reaginic serum. Pretreatment with PPP of lung tissue sensitized both to birch pollen and horse dander counteracted to a similar extent the release of histamine induced by either allergen administered in sequence. The phloretin derivatives also antagonized the constrictor action of prostaglandin F2alpha on isolated human bronchi at concentrations which did not impair the responses to histamine. The low and high molecular weight derivatives of phloretin were comparably active on a weight basis in both experimental systems.

Bronchial Spasm