==================================BSR25================================== 25. Interleukin-2 and effects on liver and gastrointestinal tract. 1 UI - 87082063 AU - Dillon SB ; MacDonald TT TI - Functional characterization of Con A-responsive Lyt2-positive mouse small intestinal intraepithelial lymphocytes. AB - The surface phenotypes of resting vs Con A-stimulated intraepithelial lymphocytes (IEL) from mouse small intestine were directly determined by immunofluorescence with double labelling. Both Thy 1.2+, Lyt 2+ and Thy 1.2+ Lyt 2- IEL underwent blastogenesis and expressed interleukin-2 (IL-2) receptors. The Lyt 2+ subsets of IEL (which represent 80% of the total cells) were isolated by panning and shown to proliferate in response to Con A and IL-2, although the frequency of responsive precursors was dramatically lower than that seen in the splenic Lyt 2+ T-cell population (1 in 500 vs 1 in 8, respectively). Con A-stimulated Lyt 2+ IEL produced lymphokines supporting the growth of the interleukin-3 (IL-3)-dependent cell line DA-1, and of the FDC-P2 cell line that proliferates in response to both IL-3 and GM-CSF. The results therefore support the possibility that Lyt 2+ IEL act as inducers of local cell-mediated immune reactions by producing haematopoietic lymphokines. MH - Animal ; Antigens, Ly/*IMMUNOLOGY ; Antigens, Surface/*IMMUNOLOGY ; Concanavalin A/PHARMACODYNAMICS ; Female ; Interleukin 2/IMMUNOLOGY ; Interleukin 3/IMMUNOLOGY ; Intestine, Small/*IMMUNOLOGY ; Lymphocyte Transformation ; Lymphokines/BIOSYNTHESIS ; Male ; Mice ; Mice, Inbred Strains ; Mitosis/DRUG EFFECTS ; Phenotype ; Rats ; Rats, Inbred Strains ; T Lymphocytes/*IMMUNOLOGY SO - Immunology 1986 Nov;59(3):389-96 2 UI - 87078973 AU - Ebert EC ; Roberts AI ; Brolin RE ; Raska K TI - Examination of the low proliferative capacity of human jejunal intraepithelial lymphocytes. AB - The proliferation of human jejunal intraepithelial lymphocytes (IEL) was examined to determine how it differed from that of peripheral blood (PB) T lymphocytes. The IEL were mainly T lymphocytes of the cytotoxic-suppressor (T8+) phenotype. They demonstrated lower proliferative responses to various stimuli (2,501 +/- 565 ct/min with phytohaemagglutinin; PHA) compared to unseparated PB T lymphocytes (73,678 +/- 2,495) or the T8+ subset (68,939 +/- 10,053 ct/min) (P less than 0.001). This low proliferative response was also a characteristic of the T8+ T lymphocytes in the lamina propria (4,606 +/- 1,226 ct/min) but not the T4+ subset (43,447 +/- 10,188 ct/min) (P less than 0.05). These findings were not due to isolation techniques or to differences in kinetics. Mixing experiments revealed that the IEL did not contain cells which suppressed proliferation. In addition, the IEL could be stimulated by mitogens, as they produced the same amount of interleukin 2 (IL-2) and IL-2 receptors as did PB T lymphocytes. Although the lectin-induced proliferative response of IEL was unaltered by the addition of autologous macrophages and minimally increased by IL-2, it was markedly enhanced by the addition of sheep red blood cells (SRBC). The enhancing effect of SRBC was not due to T cell recognition of xenogenic antigens on the erythrocytes since neither allogeneic non-T lymphocytes nor other xenogenic erythrocytes produced the same effect. Both intact SRBC and membrane fragments from osmotically lysed cells augmented lymphocyte proliferation. Thus, jejunal IEL could be activated by mitogen and proliferated as much as PB T lymphocytes if exposed to a membrane component found on SRBC. MH - Adult ; Concanavalin A/PHARMACODYNAMICS ; Erythrocytes ; Female ; Human ; In Vitro ; Interleukin 2/BIOSYNTHESIS ; Intestinal Mucosa/IMMUNOLOGY ; Jejunum/*IMMUNOLOGY ; Lymphocytes/*IMMUNOLOGY ; Male ; Mitomycins/ PHARMACODYNAMICS ; Mitosis/DRUG EFFECTS ; Phytohemagglutinins ; Receptors, Immunologic/BIOSYNTHESIS ; Support, Non-U.S. Gov't ; Suppressor Cells/IMMUNOLOGY ; T Lymphocytes/IMMUNOLOGY ; T Lymphocytes, Cytotoxic/IMMUNOLOGY SO - Clin Exp Immunol 1986 Jul;65(1):148-57 3 UI - 87056083 AU - Mathew RC ; Boros DL TI - Anti-L3T4 antibody treatment suppresses hepatic granuloma formation and abrogates antigen-induced interleukin-2 production in Schistosoma mansoni infection. AB - In murine schistosomiasis mansoni, granulomatous inflammation is an immune response that involves egg antigen presentation to T cells in the context of class II major histocompatibility complex determinants and subsequent inflammatory lymphokine production by delayed-hypersensitivity (TDH) lymphocytes. In the present study, monoclonal antibodies directed against L3T4, I-A, and Lyt-2 molecules were injected intraperitoneally into S. mansoni-infected mice to study the role of these membrane antigens in the process of granuloma formation. A dramatic suppression of the hepatic granuloma size and antigen-induced interleukin-2 (IL-2) production by spleen cells was seen in mice that received anti-L3T4 monoclonal antibody treatment. The total number of cells, especially the L3T4+ T cells, was greatly diminished in the spleens. Furthermore, histopathological study of the granulomas in stained liver sections demonstrated the paucity of eosinophils and macrophages, absence of epithelioid cells and multinucleated giant cells, and minimal collagen deposition within the lesions. Damaged hepatocytes were also seen surrounding these ill-formed granulomas. In contrast, anti-I-A monoclonal antibody treatment partially suppressed IL-2 production, although granuloma size and cellular composition remained the same. Mice that received anti-Lyt-2 monoclonal antibody did not show any changes in either IL-2 production or hepatic granulomatous inflammation. The data presented in this paper indicate a crucial role for L3T4 molecules present on a subset of class II major histocompatibility complex-restricted TDH cells in IL-2 production and the generation of the granulomatous response. MH - Animal ; Antibodies, Monoclonal/IMMUNOLOGY ; Antigens, Immune Response/ IMMUNOLOGY ; Antigens, Ly/IMMUNOLOGY ; Antigens, Surface/*IMMUNOLOGY ; Female ; Granuloma/*IMMUNOLOGY ; Hypersensitivity, Delayed/IMMUNOLOGY ; Interleukin 2/*BIOSYNTHESIS ; Liver/IMMUNOLOGY/PATHOLOGY ; Lymphocyte Transformation ; Mice ; Mice, Inbred CBA ; Schistosomiasis Mansoni/ *IMMUNOLOGY/PATHOLOGY ; Spleen/IMMUNOLOGY/PATHOLOGY ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*IMMUNOLOGY SO - Infect Immun 1986 Dec;54(3):820-6 4 UI - 87054213 AU - Aihara Y ; B:uhring HJ ; Aihara M ; Klein J TI - An attempt to produce "pre-T: cell hybridomas and to identify their antigens. AB - With the aim of identifying some of the stages in the development of pre-T cells (cells of the T cell lineage before they enter the thymus), we have produced a large number of hybridomas by the fusion of BALB/c bone marrow cells, bone marrow cells from BALB/c-nu/nu mice, BALB/c fetal liver cells and BALB/c fetal thymocytes with the AKR thymoma BW5147. The hybridomas were selected for the expression of the Thy-1.2 antigen of the normal cell donor and for their ability to produce interleukin 2 (IL 2) upon co-culture with irradiated normal spleen cells. A set of these hybridomas is described in this communication. The hybridomas were then used to immunize rats and to generate monoclonal antibody-producing B cell hybridomas. Most, if not all, of the immunizing hybridomas were derived from pre-T cells as evidenced by the fact that they produce IL 2, and express some of the T cell markers (the Thy-1.2, Ly-1, Ly-2 or L3T4 antigens). The monoclonal antibodies were tested on a panel of pre-T cell hybridomas and on normal cells obtained from spleen, lymph nodes, thymus and bone marrow. The testing was carried out by the microcytotoxicity assay and flow cytometric analysis. Three groups of antibodies could be distinguished. Some antibodies were broadly reactive, being positive with virtually all the clones in the pre-T cell panel and with a substantial fraction of normal lymphoid cells. The identity of the antigens detected by these antibodies remains unknown but they do not seem to correspond to any of the known cell surface markers. Other antibodies reacted only with some of the pre-T cell clones and did not react at all with normal lymphoid cells obtained from adult animals. Finally, other antibodies still reacted only with a minor subpopulation of thymocytes or of thymocytes and bone marrow cells, as well as some of the pre-T cell clones; they did not react with spleen and lymph node cells. These antibodies might be specific for cells in the prethymic phase of the T cell differentiation pathway. They should prove useful for the identification of pre-T cell markers and hence for the isolation of pre-T cells and their functional analysis. MH - Animal ; Antibodies, Monoclonal/IMMUNOLOGY ; Antigens, Surface/*ANALYSIS ; Bone Marrow/CYTOLOGY ; Cell Differentiation ; Hybridomas/*IMMUNOLOGY/ SECRETION ; Interleukin 2/SECRETION ; Liver/CYTOLOGY ; Mice ; Mice, Inbred AKR/IMMUNOLOGY ; Mice, Inbred BALB C/IMMUNOLOGY ; Mice, Nude/ IMMUNOLOGY ; Rats ; T Lymphocytes/*IMMUNOLOGY/SECRETION ; Thymoma ; Thymus Gland/CYTOLOGY SO - Eur J Immunol 1986 Nov;16(11):1391-9 5 UI - 87051272 AU - Lotze MT ; Matory YL ; Rayner AA ; Ettinghausen SE ; Vetto JT ; Seipp CA ; Rosenberg SA TI - Clinical effects and toxicity of interleukin-2 in patients with cancer. AB - Interleukin-2 (IL-2) is a 15,000 dalton glycoprotein produced naturally by human T-cells during an immune response. IL-2 has been demonstrated to have substantial activity alone or in combination with the adoptive transfer of lymphokine-activated killer cells in murine tumor models. IL-2 derived from both natural (Jurkat human T-cell tumor) and recombinant (Escherichia coli) sources has been studied in Phase I protocols designed to evaluate toxicity in patients with a variety of solid tumors and to ascertain improvement in clinical parameters and immunologic status. A total of 16 patients (7 with acquired immune deficiency syndrome [AIDS] and 9 with non-AIDS malignancies) were treated with Jurkat derived IL-2. The total maximum dose (1.3 X 10(5) U/kg) was limited only by supply of this reagent. A total of 25 patients have been treated with recombinant IL-2 (RIL-2) alone. Dose-limiting toxicity manifested by marked malaise and weight gain was achieved with doses of RIL-2 of 10(6) U/kg as a single bolus or 3000 U/kg/hr. IL-2 could be administered intraperitoneally with similar toxicity. Minimal renal or hepatic toxicity was demonstrated. Hematologic toxicity was limited to mild anemia (25/25), thrombocytopenia (10/25), and marked reversible eosinophilia (15/25). Pronounced weight gain greater than 2 kg (16/25) occurred in most patients, primarily those who received cumulative doses of greater than 1-3 X 10(5) U/kg of IL-2. The weight gain amounted to as much as 10% to 20% of the pretreatment weight over 3 weeks of treatment and limited our ability to give higher doses. Two partial responses (greater than 50% decrease in cross sectional diameters) were seen in two patients with melanoma metastatic to the lung. MH - Acquired Immunodeficiency Syndrome/THERAPY ; Adult ; Aged ; Biopsy ; Body Weight ; Bone Marrow/DRUG EFFECTS ; Evaluation Studies ; Female ; Human ; Interleukin 2/ADMINISTRATION & DOSAGE/TOXICITY/*THERAPEUTIC USE ; Kidney/ DRUG EFFECTS ; Liver/DRUG EFFECTS ; Male ; Middle Age ; Neoplasms/ *THERAPY ; Recombinant Proteins/TOXICITY/THERAPEUTIC USE ; Skin/PATHOLOGY SO - Cancer 1986 Dec 15;58(12):2764-72 6 UI - 86305825 AU - Rosenstein M ; Ettinghausen SE ; Rosenberg SA TI - Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. AB - Adoptive immunotherapy with lymphokine-activated killer cells and recombinant interleukin 2 (IL 2) can produce significant reduction of visceral metastases in tumor-bearing mice and, as shown recently, in humans with disseminated cancer. Because further dose escalations of IL 2 have been prevented by the development of a vascular leak syndrome (VLS) in both mice and humans, we investigated this VLS in mice undergoing the systemic administration of high-dose IL 2. A model for quantitating capillary permeability was used in which 125I-bovine serum albumin was injected i.v., and 2 hr later, tissues were counted in a gamma analyzer. A permeability index (PI) was calculated by dividing the mean counts per minute (cpm) of tissues from IL 2-treated mice by those from control animals. The injection of IL 2 produced increases in vascular permeability that were most pronounced in the thymus, spleen, lungs, liver, and kidneys (PI = 18.0, 10.0, 9.7, 6.7, and 6.3, respectively, on day 6). The development of the VLS was highly dependent on the number of days of IL 2 treatment (for example, the lungs contained 638, 1382, 3350, and 6187 cpm after 0, 1, 3, and 6 days of IL 2, respectively). Moreover, the degree of the VLS was directly related to the dose of IL 2 administered. Measurement of the wet and dry weights of lungs from IL 2-treated mice demonstrated that IL 2 produced a dramatic increase in their water weight (from 0.10 g at base line to 0.22 g after 200,000 U of IL 2 for 6 days). The injection of the IL 2 excipient failed to induce capillary leakage in tissues. Immunosuppression of mice by pretreatment irradiation (500 rad) or by injection of cyclophosphamide or by concurrent use of cortisone acetate markedly reduced or eliminated the development of the VLS. Similarly, the VLS was not observed in nude mice receiving IL 2. Thus, the administration of IL 2 produces a dose-limiting VLS that may be mediated, directly or indirectly, by host lymphoid elements. MH - Albumins/METABOLISM ; Animal ; Body Water/METABOLISM ; Capillary Permeability/*DRUG EFFECTS ; Cortisone/ANALOGS & DERIVATIVES/ PHARMACODYNAMICS ; Cyclophosphamide/PHARMACODYNAMICS ; *Extracellular Space ; Female ; Interleukin 2/PHARMACODYNAMICS/*TOXICITY ; Kinetics ; Liver/PATHOLOGY ; Lung/PATHOLOGY ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Organ Weight ; Recombinant Proteins/PHARMACODYNAMICS/TOXICITY ; Spleen/ PATHOLOGY ; Whole Body Irradiation SO - J Immunol 1986 Sep 1;137(5):1735-42 7 UI - 86250217 AU - Fung JJ ; Zeevi A ; Starzl TE ; Demetris J ; Iwatsuki S ; Duquesnoy RJ TI - Functional characterization of infiltrating T lymphocytes in human hepatic allografts. AB - We have employed recently developed techniques in T-cell culturing to study the nature and function of infiltrating hepatic allograft T cells. Using the rationale that intragraft T cells are activated during cell mediated damage to the allograft, we were able to show that these cells would propagate and remain functionally active in the presence of the T-cell growth factor, IL-2. In several instances, phenotypic analysis of cells grown in this manner was very similar to that found within the graft. Both proliferative and cytotoxic responses could be detected from the cultured cell lines. The majority of the proliferative responses were donor-directed and immunogenetic analysis could define donor-directed HLA reactivity, to either class I or class II antigens, or both. Monoclonal anti-HLA antibodies inhibition profiles verified the apparent HLA reactivity. In a smaller percentage of cases, only IL-2 responsiveness could be detected, and no HLA reactivity could be determined. Cytotoxicity could be detected against both class I and class II antigens, however, those cells which demonstrated a greater magnitude of donor-directed cytotoxicity appeared to be directed against class I antigens. A significant correlation between donor-directed proliferation of biopsy cultured lymphocytes and cellular rejection was found. This model appears to be useful in delineating functions of the intragraft T-cell population during rejection. MH - Adolescence ; Adult ; Antibodies, Monoclonal/DIAGNOSTIC USE ; Antigens, Surface/IMMUNOLOGY ; Biopsy ; Case Report ; Cells, Cultured ; Child ; Cytotoxicity Tests, Immunologic/METHODS ; Female ; Human ; HLA Antigens/ IMMUNOLOGY ; Interleukin 2/PHARMACODYNAMICS ; Liver/CYTOLOGY/PATHOLOGY/ *TRANSPLANTATION ; Lymphocyte Transformation/DRUG EFFECTS ; Major Histocompatibility Complex ; Male ; Middle Age ; Phenotype ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*PHYSIOLOGY ; Tissue Donors ; Transplantation, Homologous SO - Hum Immunol 1986 Jun;16(2):182-99 8 UI - 86236403 AU - Ohsawa M ; Masuko-Sato K ; Takahashi K ; Otsuka F TI - Strain differences in cadmium-mediated suppression of lymphocyte proliferation in mice. AB - Strain differences were investigated on the proliferative responses of splenic lymphocytes obtained from C3H/He, BALB/c, and DBA/2 mice that were treated with cadmium (Cd) for 5 days (0.5 or 1.0 mg Cd/kg/day, sc), and the results were compared with those of in vitro treatment of spleen cells with Cd. Following in vivo treatment, splenocytes from the C3H strain were significantly more susceptible to suppressive effects of Cd exposure on all indices for proliferative responses to mitogens (concanavalin A, phytohemagglutinin, and lipopolysaccharide) and allogeneic lymphocytes, while those from DBA and BALB strains were fairly resistant. Among the three strains, the highest Cd concentrations in plasma and spleen were obtained in the C3H strain with the lowest hepatic concentration of Cd. On the other hand, the Cd exposure hardly affected the splenic concentration of zinc in the C3H strain in contrast to its decrease in the others. When spleen cells obtained from normal mice were treated in vitro with Cd, the C3H strain was more resistant to the suppressive effect of Cd than the other strains. These results indicate that the mouse strain variations in Cd-mediated suppression of lymphocyte proliferation are not based on intrinsic lymphocyte sensitivities, but likely are due to differences in the metabolism of Cd, which is under genetic control. MH - Animal ; Body Weight/DRUG EFFECTS ; Cadmium Poisoning/IMMUNOLOGY/ *METABOLISM ; Injections, Subcutaneous ; Interleukin 2 ; Kidney/DRUG EFFECTS/METABOLISM ; Liver/DRUG EFFECTS/METABOLISM ; Lymphocyte Transformation/*DRUG EFFECTS ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Mice, Inbred DBA ; Organ Weight/DRUG EFFECTS ; Species Specificity ; Spleen/DRUG EFFECTS/IMMUNOLOGY/*METABOLISM ; Support, Non-U.S. Gov't ; Thymus Gland/DRUG EFFECTS/METABOLISM ; Zinc/METABOLISM SO - Toxicol Appl Pharmacol 1986 Jun 30;84(2):379-88 9 UI - 86235941 AU - Van Buren CT TI - Cyclosporine: progress, problems, and perspectives. AB - Since it much heralded debut, cyclosporine appears to have gained a major role in organ transplantation. The drug appears to have gained widespread acceptance as the immunosuppressive treatment of choice for high-risk cadaveric renal transplant recipients as well as for extrarenal organ graft recipients who depend upon a successful allograft for survival. Most centers have utilized either HPLC or RIA assays for cyclosporine levels in blood or serum to maximize immunosuppressive therapy with minimal toxicity during the critical period of induction therapy. In most patients, the balance between therapeutic and toxic effects of cyclosporine favors the immunosuppressive efficacy of the drug. Long-term consequences of cyclosporine therapy and innovative future treatment protocols will define the size of the role cyclosporine will play in the future as well as the interaction with uncast groups, such as highly presensitized patients. MH - Antibody Formation/DRUG EFFECTS ; Cyclosporins/ADMINISTRATION & DOSAGE/ TOXICITY/*THERAPEUTIC USE ; Human ; Interleukin 2/IMMUNOLOGY ; Kidney/ DRUG EFFECTS/PATHOLOGY/*TRANSPLANTATION ; Liver/DRUG EFFECTS/PATHOLOGY ; T Lymphocytes/IMMUNOLOGY ; Transplantation, Homologous SO - Surg Clin North Am 1986 Jun;66(3):435-49 10 UI - 86105882 AU - Zhang SR ; Salup RR ; Urias PE ; Twilley TA ; Talmadge JE ; Herberman RB ; Wiltrout RH TI - Augmentation of NK activity and/or macrophage-mediated cytotoxicity in the liver by biological response modifiers including human recombinant interleukin 2. AB - Administration of several biological response modifiers (BRMs) to mice strongly augmented natural killer (NK) activity of leukocytes isolated from the liver. This augmentation of NK activity was induced by two synthetic molecules (MVE-2 and poly ICLC), by two BRMs of bacterial origin (formalin-fixed Propionibacterium acnes: P. acnes and a streptococcal cell wall preparation designated OK-432), as well as a single injection of human recombinant interleukin-2 (hrIL 2). All of these BRMs augmented NK activity in the liver to a greater degree than in the spleen. In addition, adherent leukocytes (greater than 90% macrophages) isolated from the liver following P. acnes administration also exhibited augmented macrophage-mediated cytotoxicity. This cytotoxicity was characterized as macrophage mediated and distinguished from NK activity, on the basis of adherence purification, kinetics of cytotoxicity, and target cell selectivity. The results demonstrate that a variety of BRMs induce augmented natural immunity in the liver and suggest that such organ-associated immune responses may play an important role in the antimetastatic effects of BRMs. MH - Adjuvants, Immunologic/*PHARMACODYNAMICS ; Animal ; Carboxymethylcellulose/PHARMACODYNAMICS ; Cytotoxicity, Immunologic/*DRUG EFFECTS ; Female ; Human ; *Interleukin 2 ; Killer Cells, Natural/DRUG EFFECTS/*IMMUNOLOGY ; Liver/*IMMUNOLOGY ; Macrophages/DRUG EFFECTS/ *IMMUNOLOGY ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis ; Neoplasms/ IMMUNOLOGY ; Picibanil/PHARMACODYNAMICS ; Poly I-C/PHARMACODYNAMICS ; Polylysine/PHARMACODYNAMICS ; Propionibacterium acnes/IMMUNOLOGY ; Pyran Copolymer/PHARMACODYNAMICS ; Recombinant Proteins/*PHARMACODYNAMICS ; Spleen/IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Cancer Immunol Immunother 1986;21(1):19-25