transforming-growth-factor-beta and Severe-Combined-Immunodeficiency

The immune system in patients detects and eliminates tumor cells, but tumors still progress persistently. The mechanisms by which tumor cells survive under the pressure of immune surveillance are not fully understood. This review is to present the evidence from clinical studies, showing a significant correlation of clinicopathological features of carcinoma with: (1) the loss of classical human leukocyte antigen class I, (2) the up-regulation of non-classical human leukocyte antigen class I, pro-apoptotic Fas ligand and receptor-binding cancer antigen expressed on SiSo cells I, and (3) the formation of immunosuppressive microenvironment by up-regulation of transforming growth factor-beta, Galectin-1, inhibitory ligand B7s, indoleamine 2,3-dioxygenase and arginase, as well as by recruitment of tumor-induced myeloid-derived suppressor cells and regulatory T cells. All of these factors may together protect carcinoma cells from the immune-cytotoxicity.

Topics: Animals; Antigens, CD; Antigens, Neoplasm; Arginase; Fas Ligand Protein; Galectin 1; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Neoplasms; Severe Combined Immunodeficiency; T-Lymphocytes, Cytotoxic; Transforming Growth Factor beta

Regulatory T cells are critical for maintaining self-tolerance and to negatively regulate immune responses. Foxp3 is a regulatory T cell-specific transcription factor that functions as the master regulator of the development and function of regulatory T cells. Here, we report the generation of a mouse model, in which a bicistronic reporter expressing a red fluorescent protein has been knocked into the endogenous Foxp3 locus. Using this mouse model, we assessed Foxp3 expression in various lymphocyte compartments and identified previously unreported Foxp3-expressing cells. In addition, we showed that de novo Foxp3 expression along with suppressive function were induced by TGF-beta in activated CD4 T cells in vitro. Finally, we demonstrated that non-Foxp3-expressing CD4 T cells could not be converted into Foxp3-expressing cells upon adoptive transfer into immunodeficient hosts. This Foxp3 bicistronic reporter knockin mouse model should greatly enhance the study of regulation and function of Foxp3-expressing regulatory T cells.

Topics: Adoptive Transfer; Animals; Base Sequence; DNA; DNA-Binding Proteins; Forkhead Transcription Factors; Gene Expression; Genes, Reporter; In Vitro Techniques; Luminescent Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Animal; Models, Immunological; Recombinant Proteins; Red Fluorescent Protein; Severe Combined Immunodeficiency; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

In this study, we show that Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, suppresses host immune reactivity against lung cancer. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC (5 mg/kg, four times/wk i.p. for 4 wk) led to accelerated growth of tumor implants compared with treatment with diluent alone. In contrast to our findings in immunocompetent mice, THC did not affect tumor growth in tumor-bearing SCID mice. The immune inhibitory cytokines, IL-10 and TGF-beta, were augmented, while IFN-gamma was down-regulated at both the tumor site and in the spleens of THC-treated mice. Administration of either anti-IL-10- or anti-TGF-beta-neutralizing Abs prevented the THC-induced enhancement in tumor growth. Both APC and T cells from THC-treated mice showed limited capacities to generate alloreactivity. Furthermore, lymphocytes from THC-treated mice transferred the effect to normal mice, resulting in accelerated tumor growth similar to that seen in the THC-treated mice. THC decreased tumor immunogenicity, as indicated by the limited capacity for tumor-immunized, THC-treated mice to withstand tumor rechallenge. In vivo administration of a specific antagonist of the CB2 cannabinoid receptor also blocked the effects of THC. Our findings suggest the THC promotes tumor growth by inhibiting antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.

Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Antigen-Presenting Cells; Carcinoma, Lewis Lung; Cell Division; Cytokines; Dronabinol; Growth Inhibitors; Immunity, Innate; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-10; Lymphocyte Culture Test, Mixed; Lymphocyte Subsets; Lymphocyte Transfusion; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Neoplasm Transplantation; Receptors, Cannabinoid; Receptors, Drug; Severe Combined Immunodeficiency; T-Lymphocytes; Transforming Growth Factor beta; Tumor Cells, Cultured

Thrombocytopenia is a common finding in infection with equine infectious anaemia virus (EIAV), a lentivirus with some homology to human immunodeficiency virus (HIV). The thrombocytopenia of EIA, like that in some HIV patients, appears to have a multifactorial pathogenesis. To investigate the decreased platelet production seen in experimental EIA, the levels of three potential negative regulators of platelet production--tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interferon-alpha (IFN-alpha)--were measured in serum and bone marrow of six severe combined immunodeficient (SCID) foals and ten immunocompetent EIAV-infected foals. Levels of cytokines in pre-infection foal sera and bone marrow were compared with levels observed during clinical EIA. Mean serum levels of TNF-alpha and IFN-alpha were significantly higher (P < 0.05) on days -4 to 0 of thrombocytopenia than before infection. Serum TGF-beta was significantly elevated on all days except day -1 of thrombocytopenia. Bone marrow TNF-alpha levels were significantly increased in infected foals just before clinical thrombocytopenia. TGF-beta activity was not different in pre-infection and pre-thrombocytopenia bone marrows, but levels of TGF-beta protein as determined by immunohistochemical staining were significantly higher in pre-thrombocytopenia bone marrow. IFN-alpha activity in bone marrow increased just before thrombocytopenia, but the difference was not significant at P < 0.05. Serum TNF-alpha levels were 2-2.5 times higher in SCID foals on three of the days prior to thrombocytopenia than in immunocompetent foals. No significant differences were found between the levels in SCID and immunocompetent foals of serum and bone marrow TGF-beta or IFN-alpha at any of the times examined.

Topics: Acute Disease; Animals; Bone Marrow; Cytokines; Equine Infectious Anemia; Hematopoiesis; Horse Diseases; Horses; Infectious Anemia Virus, Equine; Severe Combined Immunodeficiency; Thrombocytopenia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The effect of transforming growth factor beta-1 (TGF beta 1) expression on fatty acid binding proteins was examined in control and two strains of gene targeted TGF beta 1-deficient mice. Homozygous TGF beta 1-deficient 129 x CF-1, expressing multifocal inflammatory syndrome, had 25% less liver fatty acid binding protein (L-FABP) when compared to control mice. The decrease in L-FABP expression was not due to multifocal inflammatory syndrome since homozygous TGF beta 1-deficient/immunodeficient C3H mice on a SCID background had 36% lower liver L-FABP than controls. This effect was developmentally related and specific to liver, but not the proximal intestine, where L-FABP is also expressed. Finally, the proximal intestine also expresses intestinal-FABP (I-FABP) which decreased 3-fold in the TGF beta 1-deficient/immunodeficient C3H mice only. Thus, TGF beta 1 appears to regulate the expression of L-FABP and I-FABP in the liver and the proximal intestine, respectively.

Topics: Animals; Carrier Proteins; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Fatty Acids; Gene Deletion; Gene Targeting; Inflammation; Intestinal Mucosa; Liver; Mice; Mice, Inbred C3H; Mice, SCID; Myelin P2 Protein; Neoplasm Proteins; Nerve Tissue Proteins; Severe Combined Immunodeficiency; Syndrome; Transforming Growth Factor beta; Wasting Syndrome

Transforming growth factor beta 1 (TGF beta 1)-null mice die fro complications due to an early-onset multifocal inflammatory disorder. We show here that cardiac cells are hyperproliferative and that intercellular adhesion molecule 1 (ICAM-1) is elevated. To determine which phenotypes are primarily caused by a deficiency in TGF beta 1 from those that are secondary to inflammation, we applied immunosuppressive therapy and genetic combination with the severe combined immunodeficiency (SCID) mutation to inhibit the inflammatory response. Treatment with antibodies to the leukocyte function-associated antigen 1 doubled longevity, reduced inflammation, and delayed heart cell proliferation. TGF beta 1-null SCID mice displayed no inflammation or cardiac cell proliferation, survived to adulthood, and exhibited normal major histocompatibility complex II (MHC II) and ICAM-1 levels. TGF beta 1-null pups born to a TGF beta 1-null SCID mother presented no gross congenital heart defects, indicating that TGF beta 1 alone does not play an essential role in heart development. These results indicate that lymphocytes are essential for the inflammatory response, cardiac cell proliferation, and elevated MHC II and ICAM-1 expression, revealing a vital role for TGF beta 1 in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance.

Topics: Animals; Animals, Newborn; Antibodies; Base Sequence; CD11 Antigens; DNA Primers; Genotype; Heterozygote; Homozygote; Immunotherapy; Inflammation; Leukocyte Count; Lymphocyte Activation; Lymphocytes; Mice; Mice, SCID; Molecular Sequence Data; Myocardium; Polymerase Chain Reaction; Receptors, Antigen, T-Cell, alpha-beta; Severe Combined Immunodeficiency; Transforming Growth Factor beta