concanavalin-a and Pneumonia--Pneumocystis

Initiation of the pulmonary inflammatory response to Pneumocystis carinii is delayed by 3 wk in mice infected as neonates compared with adults. There was no difference in the proliferative response of draining lymph node T cells from mice infected as neonates compared with adults when stimulated in vitro with either Con A or anti-CD3 mAB: However, TNF-alpha and IFN-gamma mRNA expression in the lungs of P. carinii-infected neonates was significantly lower than in adults indicating a lack of appropriate activation signaling in the local environment. This may have been due to active suppression because TGF-beta mRNA expression was significantly elevated in neonatal lungs compared with adults. To determine whether T cells from 10-day-old mice would effect resolution of P. carinii if harbored in an adult lung environment, cells were adoptively transferred to SCID mice with established P. carinii infections. There was no difference in the kinetics of T cell migration into the lungs or of clearance of P. carinii organisms when SCID mice were reconstituted with splenocytes from young mice as compared with adult mice. Furthermore, splenocytes from young mice stimulated both TNF-alpha and IFN-gamma mRNA expression to levels that were similar to that in the lungs of SCID mice reconstituted with adult cells. These data indicate that neonatal lymphocytes are competent to resolve P. carinii infection when harbored in an adult lung environment, suggesting that the neonatal lung environment, and not the T cells, is ineffective at responding to P. carinii infection.

Topics: Aging; Animals; Animals, Newborn; Antibodies, Monoclonal; Bronchi; CD3 Complex; Cell Movement; Cells, Cultured; Concanavalin A; Cytokines; Female; Lung; Lymph Nodes; Lymphocyte Transfusion; Mice; Mice, Inbred BALB C; Mice, SCID; Pneumocystis; Pneumonia, Pneumocystis; RNA, Messenger; Spleen; T-Lymphocyte Subsets; Trachea

We investigated the immunohematoxicities of the antiparasitic drug dapsone (DDS) and the antiretroviral drug zidovudine (ZDV, AZT) given alone or in combination in BALB/c mice. DDS is used for prophylaxis and treatment of Pneumocystis carinii infection in AIDS patients. We examined the impact of concurrent administration of these drugs on the immune and hematopoietic systems because DDS causes hematotoxicity and ZDV therapy results in bone marrow toxicity. Daily oral administration of DDS at 25 and 50 mg/kg for 28 days caused a slight anemia, marked methemoglobinemia, reticulocytosis, and a moderate leukopenia (P < 0.01 for all parameters) but had no discernible effect on platelet count. In DDS-treated mice, the proliferative response of splenic T cells to concanavalin A was > or = 35% higher than that manifested by splenocytes from vehicle-treated control mice. ZDV at 240 and 480 mg/kg was not immunosuppressive but caused low-grade macrocytic anemia, thrombocytosis, and neutropenia; these effects were drug dose-dependent and statistically significant (P < 0.01). Concurrent administration of DDS and ZDV augmented the severity of ZDV-mediated macrocytic anemia, and 7 of 12 (58%) mice did not survive treatment with the high doses of DDS and ZDV (50 and 480 mg/kg, respectively). On the other hand, co-administration of ZDV mitigated DDS-induced methemoglobinemia and the DDS-associated elevation in lymphoproliferative response. These data suggest interaction between DDS and ZDV in mice and indicate a need for caution in using DDS as long-term therapy in AIDS patients receiving ZDV.

Topics: AIDS-Related Opportunistic Infections; Anemia; Animals; Anti-HIV Agents; Antiprotozoal Agents; Bone Marrow; Concanavalin A; Dapsone; Dose-Response Relationship, Drug; Drug Interactions; Female; Leukopenia; Lymph Nodes; Lymphocyte Activation; Methemoglobinemia; Mice; Mice, Inbred BALB C; Neutropenia; Pneumonia, Pneumocystis; Thrombocytosis; Thymus Gland; Zidovudine

Donor-specific tolerance can be induced across a discordant xenogeneic barrier in T/NK cell-depleted, thymectomized (ATX) B10 mice by grafting of fetal pig thymic and liver tissue (FP THY/LIV) under the kidney capsule. We have now examined the phenotype and function of murine T cells that develop in FP THY/LIV grafts in these mice. Mouse CD4+ T cells reached normal levels in PBL by 14 wk, and were maintained up to 30 wk. Similar proportions of splenic CD4+ cells expressed the naive phenotype (CD45RBhighMEL-14+CD44low) in FP THY/LIV graft recipients and euthymic control mice. These CD4 cells were functional, demonstrating normal proliferative responses and up-regulation of CD25 and CD69 after activation by mitogens or alloantigens. They proliferated in response to the protein Ag KLH presented by host MHC following in vivo immunization. ATX B10 mice grafted with FP THY/LIV also cleared Pneumocystis carinii infections, whereas simultaneously-treated ATX B10 mice not receiving FP THY were unable to do so. Discordant xenogeneic thymus grafting can therefore restore immune competence. Thus, in addition to tolerance induction, xenogeneic thymic replacement might have a potential role in the reconstitution of immunity in patients afflicted with immunodeficiencies affecting the thymus.

Topics: Animals; Antigen-Presenting Cells; CD4-Positive T-Lymphocytes; Cell Differentiation; Concanavalin A; Fetus; Hemocyanins; Immunity, Innate; Isoantigens; Killer Cells, Natural; Liver Transplantation; Lymphocyte Activation; Lymphocyte Depletion; Lymphoid Tissue; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Pneumonia, Pneumocystis; Swine; T-Lymphocytes; Thymectomy; Thymus Gland; Transplantation Chimera; Transplantation, Heterologous

We examined T-cell proliferation in five patients with X-linked hyper-IgM syndrome (XHIM), using a panel of antigens and lectins. All patients had impaired antigen-induced proliferation, whereas their lectin responses were normal. Thus, in addition to severely depressed antibody responses, patients with XHIM have a defect in antigen-specific T-cell proliferation, which may explain their susceptibility to pathogens such as Pneumocystis carinii.

Topics: Antigens; Antigens, Fungal; Candida; CD40 Antigens; Concanavalin A; Cryptosporidiosis; Diphtheria Toxoid; Disease Susceptibility; Genetic Linkage; Humans; Hypergammaglobulinemia; Immunoglobulin M; Immunologic Deficiency Syndromes; Lectins; Ligands; Lymphocyte Activation; Male; Phytohemagglutinins; Pneumonia, Pneumocystis; Pokeweed Mitogens; T-Lymphocytes; Tetanus Toxoid; X Chromosome

Topics: Bone Marrow Examination; Candidiasis; Concanavalin A; Cytomegalovirus Infections; Fluorescent Antibody Technique; Histocompatibility Antigens; Humans; Hypersensitivity, Delayed; Immune Sera; Immunity, Maternally-Acquired; Immunoglobulins; Immunologic Deficiency Syndromes; Infant; Lectins; Lymph Nodes; Lymphocyte Activation; Male; Mitogens; Palatine Tonsil; Pedigree; Pneumonia, Pneumocystis; Thymidine; Tritium