Tamás Jánossy

Studies on the mechanism of transplantation tolerance: I. Do suppressor cells play a role in the induction and maintenance of neonatal transplantation tolerance?☆

Abstract Neonatal transplantation tolerance was induced in CBA ( H-2 k ) mice to A ( H-2 a ) mice by injection of (CBA × A)F 1 spleen cells. Animals carrying an A-skin test allograft for more than 4 months without any visible sign of rejection were considered to be permanently tolerant. Permanently tolerant CBA mice were given normal syngeneic spleen cells to abrogate the state of tolerance. Abrogation of tolerance was greatly facilitated by antithymocyte serum (ATS) treatment of tolerant mice prior to the normal syngeneic cell transfer. Survival of A allografts on normal, adult, ATS-treated CBA mice was significantly prolonged (and in many cases “adult” tolerance was achieved) by transfer of spleen cells of syngeneic mice made permanently tolerant at neonatal age. The possible role of the F 1 -cell “contamination” in the tolerance-inducing effect of the transferred “tolerant” spleen cells was excluded. The results indicate that ATS-sensitive suppressor cells play a definite role in the induction, maintenance, and transfer of neonatally induced transplantation tolerance.

Tumor cells expressing membrane-bound tumor necrosis factor activate macrophages and have a compromised growth in immunosuppressed and immunodeficient mice

Tumor necrosis factor (TNF)-alpha producing tumors as vaccines were demonstrated to induce a therapeutic anti-tumor immune response, but their clinical use is limited by the toxicity of soluble TNF. We investigated the growth characteristics and immunomodulatory properties of HeLa cells producing an uncleavable transmembrane form of TNF (preTNF). The growth of the transformed tumors was compromised in both immunosuppressed and severe combined immunodeficient mice; no signs of TNF toxicity were detected. Macrophages co-cultured with the transformed cells showed increased phagocytosis and cytokine production, indicating that activated macrophages may be the mediators of the anti-tumor effect. preTNF producing tumor cells are promising safe anti-tumor vaccine candidates.

DermAll nanomedicine for allergen-specific immunotherapy.

UNLABELLED Allergen-specific immunotherapy (ASIT) the only disease-modifying treatment for IgE-mediated allergies is characterized with long treatment duration and high risk of side effects. We investigated the safety, immunogenicity and efficacy of a novel ASIT, called DermAll, in an experimental allergic rhinitis model. We designed and characterized DermAll-OVA, a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin (OVA) as model allergen. DermAll-OVA was administered topically with DermaPrep device to target Langerhans cells. To detect the clinical efficacy of DermAll ASIT we quantified the nasal symptoms and characterized the immunomodulatory activity of DermAll ASIT by measuring cytokine secretion after OVA-stimulation of splenocytes and antibodies from the sera. In allergic mice DermAll ASIT was as safe as Placebo, balanced the allergen-induced pathogenic TH2-polarized immune responses, and decreased the clinical symptoms by 52% [32%, 70%] compared to Placebo. These studies suggest that DermAll ASIT is safe and should significantly improve the immunopathology and symptoms of allergic diseases. FROM THE CLINICAL EDITOR A novel allergen-specific immunotherapy for IgE-mediated allergies is presented in this paper, using an experimental allergic rhinitis model and a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin as model allergen. Over 50% reduction of symptoms was found as the immune systems balance was favorably altered toward more TH2-polarized immune responses.

Pathophysiological effects of human TNF‐alpha‐producing tumor xenografts in immunosuppressed mice

Groups of CBA mice immunosuppressed with antithymocyte serum (ATS) treatment were xeno‐transplanted with either HeLa human cervical carcinoma cells or genetically modified cells expressing the human tumor necrosis factor‐α (TNF) gene (All cells). Both cell lines were highly resistant to the cytotoxic effects of TNF. If 3 times 106 tumor cells were inoculated s.c. into female mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF‐expressing All cells caused fatal tumor growth only in 22% of the mice. 3times 106 or 1.5times 107 All cells produced progressive tumor growth and lethality in all male recipients. In sera of all the All‐cell‐transplanted mice, biologically active TNF was detected shortly (4.5 h) after tumor inoculation (6–39 U/ml), decreasing to below detection level in the circulation by day 3. In recipients of 15 million All cells, circulating TNF reappeared and reached high levels (12–1000 U/ml) 3 to 7 weeks later, when the animals bore large tumors (14–23 mm). Generally, such mice became cachectic, severely anemic, hypothermic, and soon died. On account of calcium mobilization from bones, their serum Ca levels were high. Electron microscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS‐treated mice xenotransplanted with TNF‐gene‐transfected All human tumor cells provide a new model for studying the pathophysiological and anti‐tumor effects of TNF.