Importance of the interaction between immune cells and tumor vasculature mediated by thalidomide in cancer treatment (Review).

Over the past 60 years, thalidomide has metamorphosized from a drug prescribed to treat morning sickness in pregnant women, which was subsequently found to induce birth defects, into a highly effective therapy for treating leprosy and multiple myeloma. Several mechanisms have been proposed to explain the anticancer effects of thalidomide, including antiangiogenic and immunomodulatory activities. At present, evidence suggests that thalidomide may induce vessel maturation. Vascular normalization may be an effective strategy to enhance cancer immunotherapy. Numerous studies have shown that the tumor infiltrating immune cell subsets are important in regulating the process of tumor angiogenesis. The mechanisms associated with antiangiogenesis and the potent immunomodulatory effects of thalidomide obtained the most support. The studies of the antiangiogenic activity of thalidomide were guided in a novel direction by a hypothesis regarding the vascular normalization of tumors. Hence, thalidomide is effective in cancer treatment due to the interaction between immune cells and tumor vasculature. This mechanism provides new avenues to explore for the treatment of cancer.

Leprosy as a model to understand cancer immunosurveillance and T cell anergy.

Leprosy is a disease caused by Mycobacterium leprae that presents on a spectrum of both clinical manifestations and T cell response. On one end of this spectrum, tuberculoid leprosy is a well-controlled disease, characterized by a cell-mediated immunity and immunosurveillance. On the opposite end of the spectrum, lepromatous leprosy is characterized by M. leprae proliferation and T cell anergy. Similar to progressive tumor cells, M. leprae escapes immunosurveillance in more severe forms of leprosy. The mechanisms by which M. leprae is able to evade the host immune response involve many, including the alterations of lipid droplets, microRNA, and Schwann cells, and involve the regulation of immune regulators, such as the negative checkpoint regulators CTLA-4, programmed death 1, and V-domain Ig suppressor of T cell activation-important targets in today's cancer immunotherapies. The means by which tumor cells become able to escape immunosurveillance through negative checkpoint regulators are evidenced by the successes of treatments, such as nivolumab and ipilimumab. Many parallels can be drawn between the immune responses seen in leprosy and cancer. Therefore, the understanding of how M. leprae encourages immune escape during proliferative disease states has potential to add to our understanding of cancer immunotherapy.

Increased tissue leptin hormone level and mast cell count in skin tags: a possible role of adipoimmune in the growth of benign skin growths.

BACKGROUND: Skin tags (ST) are common tumors. They mainly consist of loose fibrous tissue and occur on the neck and major flexures as small, soft, pedunculated protrusions. Decrease in endocrine, hormone level and other factors are thought to play a role in the evolution of ST. Leptin is an adipocyte-derived hormone that acts as a major regulatory hormone for food intake and energy homeostasis. Leptin deficiency or resistance can result in profound obesity and diabetes in humans. A role of mast cell in the pathogenesis of ST is well recognized. AIMS: To investigate the role of leptin in the pathogenesis of ST and to clarify whether there is a correlation between mast cell count and leptin level in ST. METHODS: Forty-five skin biopsies were taken from 15 patients with ST. From each patient, a biopsy of a large ST (length >4 mm), a small ST (length <2 mm) and a normal skin biopsy (as a control) were taken. The samples were processed for leptin level. Skin biopsies were stained with hematoxylin and eosin and toluidine blue-uranyl nitrate metachromatic method for mast cell count was used. RESULTS: There was a significant increased level of leptin in the ST compared to the normal skin. It was highly significant in small ST than in big ST (P = 0.0001) and it was highly significant in small and big ST compared to controls, P = 0.0001 and P = 0.001, respectively. There was a significant increase in mast cell count in the ST, which did not correlate with the increased levels of leptin. CONCLUSION: This is the first report to demonstrate that tissue leptin may play a role in the pathogenesis of ST. The significant increase in the levels of leptin and mast cell count in ST may indicate a possible role of adipoimmune in the benign skin growths.

Properties of thalidomide and its analogues: implications for anticancer therapy.

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

Immunological effects of thalidomide and its chemical and functional analogs.

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Immunological effects of thalidomide and its chemical and functional analogs

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Tumor-induced immune dysfunction.

Immune system-based approaches for the treatment of malignant disease over the past decades have often focused on cytolytic effector cells such as cytotoxic T lymphocytes (CTL), and natural killer (NK) cells. It has also been demonstrated that tumor-bearing mice can be cured using a wide variety of approaches, some of which involve cytokine-mediated enhancement of CTL and NK cell activity. However, the apparent success in mice stands in contrast to the current situation in the clinic, wherein only a minority of patients have thus far benefited from CTL- or NK cell-based antitumor approaches. The underlying causes of tumor-associated immune suppression of CTL and NK cell activity are discussed, and features of interest shared with HIV infection, leprosy, and rheumatoid arthritis are also be mentioned. Remarkable and very recent observations have shed more light upon the causes of dysfunctional alterations in CTL and NK cells often associated with these diseases, that in turn have suggested new immunotherapeutic approaches for cancer and infectious disease.

Rational immunotherapy with interleukin 2.

Interleukin 2 (IL-2), a T lymphocyte product released upon antigen stimulation, has been used for cancer therapy in high doses for more than five years. More recently, its potential as a stimulant of cell-mediated immunity in infectious diseases, particularly those caused by intracellular microbes, has become appreciated. Drawing on the extensive information available as to the structure, cellular and molecular effects of IL-2, this review focuses on its use in patients with lepromatous leprosy and AIDS in low, physiologic doses. The data indicate that IL-2 is effective in stimulating cell-mediated immunity without systemic toxicity.

[Isolation and characterization of immune complexes associated with malignant tumors and leprosy]. / Aislamiento y caracterización de complejos inmunes asociados a tumores malignos y a lepra.

We are dedicated to the study of circulating immune complexes (CIC) associated with different diseases: malignant tumors, leprosy and rheumatoid arthritis. Immune complexes were evaluated by various methods: 125I-Clq binding assay, 125I-IgG binding test, 125I-bovine conglutinin binding assay and polyethylene glycol precipitation test (3.5% and 2.5%). Techniques for the isolation and splitting of CIC in their components were performed in sera from patients with tumors and with leprosy. These methods consisted in the combination of CIC with protein A followed by elution with different buffers. CIC splitting techniques were first applied on immune complexes formed in vitro (BSA-aBSA, OVA-aOVA). The analysis of CIC fractions was done by SDS-PAGE, immunoelectrophoresis and immunoblotting techniques. Results were as follows: CIC levels correlated with active stages of disease, decreasing during remission so that CIC detection can be useful to evaluate response to treatment. The isolation and splitting of immune complexes into their components resulted in the obtention of immunologically active fractions, especially in sera from patients with gastrointestinal and breast cancer and with leprosy.

Aislamiento y caracterización de complejos inmunes asociados a tumores malignos y a lepra / Isolation and characterization of immune complexes associated with malignant tumors and leprosy

Hemos estudiado los complejos inmunes circulantes (CIC) asociados a diversas enfermedades tales como neoplasias malignas, lepra y artritis reumatoidea. Se realizó la detección de CIC empleando diferentes técnicas: test de combinación a 125I-Clq, a IgG radioactiva, a conglutinina bovina marcada, test de aglutinación de plaquetas y precipitado en polietilen glicol 3,5% y 2,5%. Posteriormente, se desarrollaron técnicas de asislamiento y separación de los CIC para la obtención de sus fracciones constituyentes en ciertos tumores malignos y en lepra, basadas en la afinidad de los CIC por proteína A y en la acción de diferentes buffers. Estos métodos se aplicaron previamente a complejos inmunes preparados in vitro (BSA-aBSA, OVA-aOVA, etc.). El análisis de las fracciones se realizó por SDS-PAGE, inmunoelectroforesis, inmunoblotting, etc. Los resultados fueron los siguientes: se observó una elevada incidencia de niveles de CIC positivos coincidentes con los estadios de actividad clínica, disminuyendo en la remisión. Así mismo en algunos grupos de pacientes los hallazgos de CIC permitieron evaluar la eficacia terapéutica. Con el desarrollo de técnicas de separación de CIC se obtuvieron fracciones inmunológicamente activas provenientes de los CIC aislados del suero de pacientes portadores de tumores malignos, especialmente del tubo digestivo y de mama y posteriormente en el suero de individuos con lepra. Los resultados obtenidos hasta la fecha han demostrado la utilidad clínica de los estudios...

Aislamiento y caracterización de complejos inmunes asociados a tumores malignos y a lepra / Isolation and characterization of immune complexes associated with malignant tumors and leprosy

Hemos estudiado los complejos inmunes circulantes (CIC) asociados a diversas enfermedades tales como neoplasias malignas, lepra y artritis reumatoidea. Se realizó la detección de CIC empleando diferentes técnicas: test de combinación a 125I-Clq, a IgG radioactiva, a conglutinina bovina marcada, test de aglutinación de plaquetas y precipitado en polietilen glicol 3,5% y 2,5%. Posteriormente, se desarrollaron técnicas de asislamiento y separación de los CIC para la obtención de sus fracciones constituyentes en ciertos tumores malignos y en lepra, basadas en la afinidad de los CIC por proteína A y en la acción de diferentes buffers. Estos métodos se aplicaron previamente a complejos inmunes preparados in vitro (BSA-aBSA, OVA-aOVA, etc.). El análisis de las fracciones se realizó por SDS-PAGE, inmunoelectroforesis, inmunoblotting, etc. Los resultados fueron los siguientes: se observó una elevada incidencia de niveles de CIC positivos coincidentes con los estadios de actividad clínica, disminuyendo en la remisión. Así mismo en algunos grupos de pacientes los hallazgos de CIC permitieron evaluar la eficacia terapéutica. Con el desarrollo de técnicas de separación de CIC se obtuvieron fracciones inmunológicamente activas provenientes de los CIC aislados del suero de pacientes portadores de tumores malignos, especialmente del tubo digestivo y de mama y posteriormente en el suero de individuos con lepra. Los resultados obtenidos hasta la fecha han demostrado la utilidad clínica de los estudios... (AU)

Immunology in Malaysia--a review.

Immunology is a discipline that traverses all branches of clinical medicine. Thus since about ten years ago major hospitals in Malaysia established routine clinical immunology services particularly in the diagnosis of autoimmune/connective tissue disorders. More recently these laboratories have ventured into basic research in Dengue Haemorrhagic Fever, Leukaemia Immunology, Nasopharyngeal Cancer and Leprosy. The rationale for these projects together with early results from them are discussed.

Serological survey of leprosy and control subjects by a monoclonal antibody-based immunoassay.

A serological antibody competition test (SACT) using a murine anti-Mycobacterium leprae-specific monoclonal antibody (ML04) has been evaluated in 96 untreated leprosy patients and 128 control subjects. The test is based on the competitive inhibition by antibodies from human test sera of the binding of the specific 125I-ML04 murine monoclonal antibody to M. leprae soluble antigen coated microtiter plates. Along the spectrum of the disease, SACT positivity was observed in 100% of LL-BL, 87.5% of BB, and 46.7% of the TT-BT groups of patients. Moreover, 46.4% of apparently healthy household family contacts of multibacillary leprosy cases were also antibody positive. Sera from 15 contacts of paucibacillary leprosy cases as well as from 85 various nonleprosy subjects (tuberculosis, autoimmune disease, cancer, and healthy) were all found to be negative. These results satisfy the requirements of a leprosy-specific serodiagnostic test. The striking increase of antibody titer in all of the LL/BL patients indicates a potential prognostic utility of this test for the lepromatous shift of the disease. The observed positivity in a fraction of healthy leprosy contacts still requires prospective evaluation of disease incidence in a larger test sample.

Specificity of antibodies to Newcastle disease virus.

Specificity of antibodies to Victoria strain of Newcastle disease virus (NDV) found in infectious mononucleosis (IM) and other pathologic sera was investigated by agglutination of NDV-modified human O red blood cells, as well as by immunodiffusion and enzyme immunoassay with various preparations of the virus. These studies clearly demonstrated that the NDV antibodies are distinct from P-B or H-D antibodies. The unexpected observation that guinea pig kidney (GPK) tissues absorbed NDV antibodies allowed their classification into a group of 'GPK-positive' heterophile antibodies. The simultaneous occurrence of the NDV antibodies and H-D antibodies in IM and other diseases suggests the possibility that multiple new antigenic determinants, especially those of carbohydrate nature, may appear due to the alteration of self-antigens as a result of various pathologic processes.

Soluble immune complexes in human disease.

The great variety in biochemical properties of immune complexes occurring in human and animal disease states has made the detection of such complexes a difficult task. Variability in immune complex size, specificity, and interaction with humoral or cellular receptor systems, such as complement and phagocytes, suggests different pathogenic properties. The introduction of radioimmunoassays and the recently improved knowledge of the immune complex-receptor interactions have lead to the description of a large number of detection procedures, which in turn has widened the catalogue of diseases associated with immune complexes. This widespread occurrence of soluble immune complexes has lead many investigators to think that such complexes may occur either as a transient physiological phenomenon, important for fast clearance of the antigen, or as primary pathogenic factors triggering inflammatory reactions. Among the 50 procedures for immune complex detection known today, the article will select some pertinent tests, which will be discussed with respect to their specificity, sensitivity, and reproducibility. Furthermore, it is well known that when applied to the study of a patient group with one particular immune complex disease, various tests will result in different percentages of patients having complexes. This observation is due to differences in the underlying principle on which the various tests are based. Thus immune complexes must be further characterized with respect to their size, to the antibody class or specificity involved and, most difficult, to the antigenic specificity which participates in the complex. Recent advances in such experimental characterization of immune complexes in vitro and in the clinical evaluation of patients with complement activation associated to the presence of immune complexes will be discussed.