The effects of the immunosuppressive drugs cyclophosphamide (CyP), cyclosporin A (CsA) and the Langerhans cells immunomodulator OK-432, a bacterial cell wall preparation, on herpes simplex virus type-1 (HSV-1) infection in mice were studied. An increased mortality of HSV-1-infected mice was observed following intraperitoneal injection of both the pathogenic HSV-1 (Justin) and the apathogenic UL56-deleted HSV-1-M-LacZ strains. Intraperitoneal injection of CyP prior to infection with HSV-1 increased the susceptibility to infection of normally resistant mouse strains, including the inbred strain C57BL/6 and the outbred Sabra strain, with the virus reaching the pancreas, the spinal cord and the spleen. Polymerase chain reaction (PCR) to detect viral DNA in mouse organs following IP HSV-1 injection after treatment with CyP and/or OK-432 showed that CyP treatment prevented the virus from reaching the pancreas, while a combination treatment of both chemicals allowed HSV-1 to reach the pancreas. These studies indicate that treatment of mice with immunosuppressive drugs (CyP and CsA), which affect dendritic cells and T cells, prevents the migration of HSV-1 to the pancreas, while the immunomodulator OK-432, which induces dendritic cell activity, did not prevent virus migration to the pancreas. Lung samples were consistently positive for viral DNA following treatment with either CyP or CsA. PCR to detect viral DNA in mice injected with HSV-1 via the footpad route following pretreatment with CyP and OK-432 also through the footpad revealed the presence of HSV-1 DNA in the spinal cord on days 1, 3, and 5 post-infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

PubMedDate not supplied

Success and failure of dendritic cell (DC) anticancer activity may be modulated by nitric oxide synthetase (NOS) gene expression: a hypothesis.

Observations during the last several years on the relationships between bone marrow-derived dendritic cells (DC) and the cells which are in direct contact with them led to the idea that DC may have regulatory properties. Such regulatory properties exerted by DC were noted in experimental cancers in murine systems as well as in human cancers. It was noted that patients with the same type of cancer in which DC are present in the tumor survive longer than patients without DC in the tumor. It is not known how DC can abrogate the development of the metastatic tumor cells in the primary tumor, nor how the tumor cells are capable of abrogating the anticancer activity of the DC and allowing the development of tumor metastases. Studies on the anticancer activity of macrophages revealed that these cells have an inducible Nitric Oxide (NO) synthase (NOS) which utilizes arginine to produce NO. Suppressor macrophages release NO, which inhibits the ribonucleotide reductase and mitochondrial oxidation in tumor cells in vitro. It was also reported (4) that Interferon gamma (IFN-gamma), produced by murine T helper 1 cells, induces NOS activity in macrophages, while T helper 2 cells which produce Interleukin-4 (IL-4) inhibit the expression of NOS in macrophages. The hypothesis presented in this paper suggests that DC have a gene for NOS which is inducible by immunomodulators (e.g. IFN gamma, OK432, LPS) and can be suppressed by cytokines produced by tumor cells (e.g. IL-4, IL-10).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMedDate not supplied

Dendritic cell activity against primary tumors: an overview.

Bone marrow-derived dendritic cells (DC) function as antigen presenting cells (APC). Little is known of their capability to exert regulatory effects on the epithelial cells in various organs. It was reported that injection of the bacterial cell wall preparation OK432 into mouse skin resulted in the activation of IL-1 and TNF-alpha gene expression in Langerhans cells (LC). In addition to studies on LC/DC in normal tissues, numerous investigators reported that DC can infiltrate primary tumors in experimental animals and humans and cause tumor regression. Human tumors in which DC infiltrates were detected did not develop metastases. The presence of DC in tumor biopsies correlated with the survival of patients. Absence of DC from tumors suggested poor prognosis. Activation of DC by immunomodulators seemed to enhance the ability of DC to prevent the development of metastatic tumors. Information on the role of DC as anticancer cells was recently reviewed, but information on the molecular basis of the anticancer activity of DC is needed. Another problem which needs to be answered is the ability of some tumors to prevent DC from entering the tumor. It is possible that DC and tumor cells, interact and counteract by releasing cytokines which abrogate tumor cells or DC, respectively. In the present analysis the DC responses to extrinsic cytokines and immunomodulators will be discussed. The ability of DC to induce the expression of the nitric oxide synthase gene will be discussed in relation to the anticancer activity of DC and in comparison with the reported anticancer activity of macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Role of Langerhans cells and other dendritic cells in disease states.

Langerhans cells belong to the dendritic cell lineage and function as potent antigen-presenting cells in the skin epidermis. During the last decade, much has been learned on dendritic cell involvement in the pathogenesis of disease states. This review briefly summarizes our current understanding of the role played by Langerhans cells and other dendritic cells in the pathogenesis of immune-mediated, neoplastic and infectious disorders.

Communicable Diseases↗

PubMedDate not supplied

Bone marrow-derived dendritic cells and the protection against X-ray-induced thymic leukemia in mice. A new interpretation.

About forty years ago, Henry Kaplan and collaborators reported that four weekly X-ray doses of 160 rads each were highly leukemogenic in C57BL mice. A single dose of 350 Rads had a week leukemogenic effect. These authors also demonstrated that lead shielding of the thigh during irradiation prevented the development of leukemia. They reported that intravenous injection of syngeneic bone marrow cells into irradiated mice facilitated the regeneration of the thymus and prevented the development of X-ray-induced tumors. We characterized the thymic Ia+ dendritic cells (DC) with the aid of a fluorescence-activated cell-sorter (FACS). It was found that exposure of mice to a leukemogenic regimen of fractionated X-irradiation treatment led to a gradual decrease in the number of thymic DC. The disappearance of thymic DC and the development of leukemia were prevented by intravenous injection of syngeneic bone marrow or by lead shielding of the femur during irradiation. These results indicated that the fractionated irradiation caused a decline in the number of DC and, as a result, diminution of the natural defense against the developing tumor. Homing of the injected bone marrow DC into the thymus can be connected to the prevention of tumor development. Since leukemogenic T cells produce interleukin-4(IL-4), we tested the effect of the conditioned medium in which YAB-3 cells (tumorigenic Th cells: CD4+, CD8-, Thy-1+) were cultivated. Following injection of the conditioned medium into the mouse footpads, the number of skin Langerhans cells (LC) decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Immunomodulation by OK-432 and calcitonin gene-related peptide (CGRP) of nitric oxide synthase (NOS) and IL-1 beta gene expression and of HSV-1 pathogenicity in mouse skin Langerhans cells (LC).

The effect of HSV-1 infection in the epidermis on the expression of genes for nitric oxide synthase (NOS) and interleukin-1 beta (IL-1 beta), and the ability of OK-432 to alter this effect were studied. The genes for NOS and IL-1 beta are normally expressed in Langerhans cells as well as in keratinocytes. Neither administration of OK-432 nor infection with HSV-1 abrogates this gene expression. Calcitonin gene-related peptide (CGRP) can inhibit the ability of macrophages and Langerhans cells to act as antigen-presenting cells. The effect of treatment with CGRP on mouse footpads and subsequent infection with HSV-1 was studied and compared with the effects observed after treatment with a specific antagonist for CGRP. Viral DNA was detected in adrenal gland samples of mice treated with the virus only and of mice treated with either CGRP-(1-37) or its antagonist prior to injection of the virus. In spinal cord samples, viral DNA was only detected when mice were treated with the virus or the CGRP antagonist. CGRP-(1-37) at physiological concentrations does not enable HSV-1 injected into mouse footpad skin to reach tissues which are normally resistant.

Animals↗