Kaiser He

Review of thymic hormones in cancer diagnosis and treatment.

The thymus is an endocrine organ. A unified, physiological concept of humoral regulations of the immune response has emerged in the last three decades. The thymus is the major site of production of immunocompetent T lymphocytes from their hematopoietic stem cells. This complex process required direct cell to cell, receptor based interactions, as well as in situ paracrine information via the numerous cytokines and thymic hormones produced by the cells of thymic microenvironment. Thymic hormones induce in situ T-cell marker differentiation, expression and functions. These polypeptide hormones have also been shown by means of immunocytochemistry to localize in the reticulo-epithelial (RE) cells of the thymic cellular microenvironment. Due to the great complexity of the intrathymic maturation sequence of T lymphocytes and the diverse immunophenotypically unique subpopulations of T lymphocytes, it is quite unlikely that a single thymic humoral factor could control all of the molecular steps and cell populations involved. It is much more likely that an extremely rich and diverse, but genetically determined, milieu is present within the thymus, and that thus the control of intrathymic T lymphocyte maturation and the functional maturation of T cells involves the orchestral interaction of various thymic-specific factors and other molecules during the differentiation process. Thymosin fraction 5 and its constituent peptides influence several properties of lymphocytes including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, as well as the expression of various cell surface maturation/differentiation markers. Recently, derivatives of thymic hormones, mostly of thymosins, have been detected as products of neoplastically transformed cells and employed in the early diagnosis of neoplasms. In clinical trials, thymic hormones strengthen the effects of immunomodulators in immunodeficiencies, autoimmune diseases, and neoplastic malignancies. Combined chemo-immunotherapeutical anti-cancer treatment seems to be more efficacious than chemotherapy alone, and the significant hematopoietic toxicity associated with most chemotherapeutical clinical trials can be reduced significantly by the addition of immunotherapy.

Murine AIDS Cured by Low Dosage Total Body Irradiation

Animal models are useful for establishing the potential efficacy of various treatment protocols. A murine hematological disease induced by Friend leukemia virus (FLV, retrovirus) is accompanied by a severe immunodeficiency syndrome termed Murine AIDS (M-AIDS) (1–3). We have demonstrated that mice infected with a lethal dose of FVC can be 100% cured by 150 cGY total body irradiation (TBI) clinical trials with AIDS patients(6).

Immunocytochemical detection of leukocyte-associated and apoptosis-related antigen expression in childhood brain tumors

During systematic cell-surface antigen expression profile analyses of 76 primary childhood brain tumors [34 medulloblastomas (MED)/primitive neuroectodermal tumors (PNETs) and 42 astrocytomas (ASTR)], a library of monoclonal antibodies (MoABs) directed against various leukocyte-associated, lymphocyte cell-line differentiation antigens in childhood brain tumors was utilized. The antigens were detected employing an indirect, biotin-streptavidin conjugated alkaline phosphatase (AP) immunocytochemical technique. Major histocompatibility complex (MHC) class I restricted, tumor-associated antigen (TAA) specific, CD8(+) cytotoxic T lymphocytes (CTL) were identified in 58/76 (76.32%) brain tumors, and usually represented 1-10% of all cells, but in some cases 30-44% of the cells were CD8(+). CD4(+), MHC class II restricted helper lymphocytes were present in 65/76 (85.53%) brain tumors, and accounted for 1-10% of the observed cells. Macrophages were present in 74/76 (97.37%) brain tumors, and their number also represented 1-10% of all observed cells in the brain tumor frozen sections. Leukocyte common antigen (LCA) expression was detected in all 76 (100%) brain tumors studied. MoAB UJ 308 detected the presence of premyelocytes and mature granulocytes in 60/76 (78.95%) brain tumors. Natural killer (NK) cells were not defined in the observed brain tumors. The great majority of childhood glial tumors, particularly ASTRs express Fas (APO-1/CD95) receptor whereas normal cells in the central nervous system (CNS) do not. FasR is a transmembrane glycoprotein which belongs to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily. As part of our screening, the 42 childhood ASTRs were also investigated for expression of CD95. We detected strong expression (strong intensity of staining, number of stained cells 50-100%) of FasR, employing formalin fixed, paraffin-wax embedded tissue slides. Brain tumors and melanomas have been shown to produce their autocrine FasL, and are even capable of switching CD95-related signal transduction from the PCD pathway to a proliferative pathway. In view of our results, we conclude that: (1) the tumor infiltrating leukocytes in MEDs/PNETs and ASTRs represent a very diverse population and are present in a great majority of the cases studied; (2) the strong expression of FasR in ASTRs provides a manner in which T lymphocytes may exert their anti-tumor effects, but may also represent yet another way that tumors may evade the immune response; and (3) further observations of the expression of various antigens involved in juxtacrine, in situ growth control are necessary for the refinement of cellular immunotherapeutical approaches in the treatment of human malignancies.

Selected aspects of cancer progression : metastasis, apoptosis and immune response

Chapter 1: Metastasis: A Current Perspective David T. Denhardt, Ann F. Chambers, Danny R. Welch Chapter 2: Control of Cell Motility during Tissue Invasion James Varani Chapter 3: Cell adhesion and invasion during secondary tumor formation Peter Gassmann, Jorg Haier and Garth L. Nicolson Chapter 4: Genes and Metastasis Alison L. Allan and Ann F. Chambers Chapter 5: The evolution of diversity within tumors and metastases Rakesh K. Singh and James E. Talmadge Chapter 6: Tumor angiogenesis, antiangiogenic therapy and anti-antiangiogenesis response Mengfeng Li Chapter 7: Apoptosis and Cancer Laszlo Kopper, Istvan Petak Chapter 8: Macrophages in Tumour Development and Metastasis Alexandra Eichten, Karin E. de Visser, Lisa M. Coussens Chapter 9: Classical and alternative activation of macrophages: different pathways of macrophage-mediated tumor promotion Jo Van Ginderachter, Yuanqing Liu, Nick Devoogdt, Wim Noel, Lea Brys, Gholamreza Hassanzadeh Gh., Geert Raes, Anja Geldhof, Alain Beschin, Hilde Revets and Patrick De Baetselier Chapter 10: Characterization of tumor-directed cellular immune responses in humans Dirk Nagorsen, Vladia Monsurro and Francesco M. Marincola Chapter 11: Abnormal variation of the immune response as related to cancer Gerhard R.F. Krueger and Maximilian Buja Chapter 12: Immunological Aspects of Mareks Disease Virus (MDV)-induced Lymphoma Progression Mark S. Parcells and Shane C. Burgess Chapter 13: A Biodynamical Model of Human T-Cell Development and Pathology: Design, Testing and Validation Michael E. Brandt, Gerhard R. F. Krueger and Guanyu Wang

THE THERAPEUTIC EFFECT OF NATURIN-2 ON LEWIS LUNG CARCINOMA AND MURINE-AIDS

The immune system plays a major role in immuno-surveillance, and its impairment has been linked to cancer and immuno-deficiency disorders including AIDS. (1–3) The biological response modifier (BRM) is a term used for an agent whose antitumor effects were thought to be exerted through modulation of the host’s immune system, as contrasted with the antitumor effects of traditional chemotherapeutic drugs and irradiation which kill cancer cells directly. The BRMs are synthetic compounds or naturally occurring proteins that alter host immune responses and have been applied to a broad range of agents including cytokines. These cytokines include, but are not limited to, the interferons, the inter-leukins, the tumor necrosis factors, the hematopoietic colony stimulating factors, etc. More recent studies in our laboratory have demonstrated the potential of the interleukins and colony stimulating factors to decrease the metastatic potential of the B16 melanoma and the Lewis Lung Carcinoma and potential usefulness is that mice infected with the retrovirus (Friend Virus) can be rescued from death. This treatment was associated with restoration of immunosuppression and enhancement of immune function. The cytokines can act in greater than additive fashion and combinations of therapies are possible. (3–6)