Improvement of the lymphoproliferative immune response and apoptosis inhibition upon in vitro treatment with zinc of peripheral blood mononuclear cells (PBMC) from HIV+ individuals

Clinical improvement has been described in AIDS patients submitted to zinc therapy, but the mechanisms involved are not well understood. In order to evaluate the effect of the zinc ions in the enhancement of the immune response, we tested its role in the lymphoproliferative response to a mitogen, as well as in the prevention of apoptosis. The mitogenic effect of zinc (10^?4 m ZnCl₂) on the lymphocyte proliferative response was observed in healthy controls as well as in HIV-1⁺ asymptomatic individuals. Very low stimulation index could be observed in AIDS patients (CD4⁺ < 200/mm³). However, zinc treatment of phytohaemagglutinin (PHA; 5 μg/ml)-stimulated PBMC cultures significantly enhanced ³H-thymidine incorporation in both asymptomatic and symptomatic groups. A decreased percentage of apoptotic cells could be identified in cell cultures from HIV-1⁺ individuals submitted to zinc treatment compared with cells treated only with PHA, as detected by both flow cytometry and agarose gel electrophoresis. Further studies with zinc supplementation associated to anti-retroviral therapy would be of great interest to evaluate the in vivo role of this oligoelement in the improvement of the immunological functions of HIV-1-infected individuals and AIDS patients.     

Specific and Nonspecific Cooperation Between M-Locus-Incompatible T and B Cells During Adoptive Anti-Hapten Antibody Responses in Mice

CBA and AKR mice are identical at the major histocompatibility locus (H-2) but differ at the strong, non-H-2, mixed leukocyte culture (MLC)-stimulating M-locus. Adoptive secondary in vivo antibody responses using immune spleen cells from mice of these strains demonstrate two interesting findings. One is a non-specific augmentation of the anti-hapten antibody response of CBA B cells by AKR T cells. This allogeneic effect is unidirectional in the same sense as the MLC between cells from these two strains. The second is that, despite an ongoing allogeneic effect, M-locus-incompatible T and B cells show strong specific cooperation. Thus, it seems unlikely that the failure of H-2-incompatible T and B cells to collaborate specifically is due to inhibitory allogenic reactions.     

Early central nervous system complications after reduced-intensity stem cell transplantation.

To investigate clinical characteristics of early central nervous system (CNS) complications after reduced-intensity stem cell transplantation (RIST), we reviewed the medical records of 232 patients who had undergone RIST for hematologic diseases at our institutions between September 1999 and June 2003. All patients had received purine analog-based preparative regimens. Stem cell sources comprised granulocyte colony-stimulating factor-mobilized blood from HLA-identical or 1 locus-mismatched related donors (n = 151), unrelated bone marrow (n = 44), or unrelated cord blood (n = 37). Graft-versus-host disease prophylaxis incorporated cyclosporine with or without methotrexate. Diagnosis of CNS complications was based on clinical, radiologic, and microbiological findings. CNS complications occurred in 18 patients (7.8%), with a median onset of 22 days, and were infectious (n = 1), metabolic (n = 15), or cerebrovascular (n = 2). Symptoms included seizures (n = 7), visual disturbance (n = 2), headache (n = 8), nausea (n = 8), vomiting (n = 6), impaired consciousness (n = 16), and hemiparesis (n = 3). Complications improved promptly in 10 patients, and 8 patients died without improvement within 30 days. Multivariate analysis with logistic regression identified umbilical cord blood transplantation as a significant risk factor for early CNS complications (odds ratio, 14.5; 95% confidence interval, 3.7-56.9; P <.0001). CNS complications are a significant problem after RIST, particularly with umbilical cord blood. Limbic encephalopathy is an unrecognized subtype of neurotoxicity after umbilical cord blood transplantation.     

Effects of Cl-949, a Novel Antiallergy Compound, on Host Resistance in Mice

Effects of CI-949, a Novel Antiallergy Compound, on Host Resistancein Mice. BLEAVINS, M. R., MARTIN, R. A., DE LA IGLESIA, F. A.,MUNSON, A. E., MCCAY, J. A., FOUANT, M. M., AND WHITE, K. L.,JR. (1991). Fundam. Appl. Toxicol. 17, 723–732. The effectof CI-949, a novel inhibitor of allergic mediator release, onimmune function was assessed with holistic mouse models of immunocompetence.Resistance to the bacterial pathogens Listeria monocytogenesand Streptococcus pneumoniae and the B16F10 melanoma cell linewas used to evaluate the potential of CI-949 to affect immunefunction. CI-949 treatment of female B₆C₃F₁, mice increasedpulmonary tumor burden at 100 mg/kg/day in the B16F10 melanomamodel, with a no effect level of at least 50 mg/kg/day. A correlationwas seen between decreased clearance of the B16F10 cells andincreased tumor burden. However, CI-949 produced this effectonly at the maximum tolerated dose. No effect of the drug wasseen in the S. pneumoniae model. Host resistance to L. monocytogeneswas increased after CI-949 administration, with the no adverseeffect level in this model being at least equivalent to thetop dose of 100 mg/kg/day. Therefore, the immune system doesnot appear to be adversely affected or to be a specific targetfor CI-949 even at an overtly toxic.     

The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non- SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.      

Expression of Toxoplasma gondii-Specific Heat Shock Protein 70 during In Vivo Conversion of Bradyzoites to Tachyzoites

Stage conversion between bradyzoites and tachyzoites was investigated in C57BL/6 mice chronically infected with the ME-49 strain of Toxoplasma gondii. In order to promote bradyzoite-tachyzoite conversion, mice were treated in vivo with neutralizing doses of anti-gamma interferon (IFN-γ) or anti-tumor necrosis factor alpha (TNF-α) antibodies. Expression of parasite-specific antigens SAG-1, SAG-2, and heat shock protein 70 (Hsp-70) was visualized in the central nervous system by immunocytochemistry and measured by photometric assay. The immunosuppressive effect of anti-IFN-γ or anti-TNF-α treatment was immediate, leading to parasite stage conversion as indicated by the increased expression of tachyzoite-specific antigens (SAG-1 and SAG-2) and by rapid parasite replication. We also observed expression of high levels of Hsp-70 during a short period of conversion of bradyzoites to tachyzoites. Our data suggest that Hsp-70 may have an important role in the process of bradyzoite-tachyzoite conversion during the reactivation of chronic toxoplasmosis.