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Biomedical subjects

R D Granstein

Publications and source records attributed to R D Granstein.

At least 91 records · Page 5Linked to original sources
PubMed1987

Whole-body exposure to ultraviolet radiation results in increased serum interleukin-1 activity in humans.

Human volunteers given one minimal erythemal dose of ultraviolet radiation (UVR) from fluorescent sunlamps developed increased serum interleukin-1 (IL-1) activity as assessed by the thymocyte co-stimulator assay. This activity peaked 1 to 4 hours after exposure and returned to baseline by 8 hours after exposure. Six to 12 months later, some of the same subjects had blood samples taken over the same time course but without exposure to UVR; no elevation in serum IL-1 was observed. In addition to lymphocyte activating activity, IL-1 has been reported to have endogenous pyrogen activity, chemotactic activity for neutrophils and mononuclear cells, and inflammatory activity when injected subcutaneously in vivo. Elevations in serum IL-1 activity after exposure to ultraviolet radiation may account for some of the manifestations of the sunburn response.

Adult↗
PubMed1986

Prolongation of murine skin allograft survival by immunologic manipulation with anti-interleukin 2 receptor antibody.

Administration of a rat monoclonal antibody (M7/20) directed against the murine interleukin 2 (IL 2) receptor in combination with sublethal x-irradiation of the recipient significantly enhanced the survival of skin allografts, both when the grafts were MHC disparate from the hosts and when only minor histocompatibility differences were present compared with untreated controls. No prolongation in graft survival was seen with either treatment alone at the dose employed. M7/20 and x-ray-treated allograft recipients also displayed significantly decreased alloantigen-specific reactivity against donor-strain spleen cells in both delayed-type hypersensitivity and cytotoxicity assays. Thus, such combination treatment reduces expression of host immune reactivity against graft determinants by several criteria. This work provides additional evidence that monoclonal antibodies directed against the IL 2 receptor may be useful in clinical transplantation.

Animals↗
PubMed1986

Enhancement of the elicitation phase of the murine contact hypersensitivity response by prior exposure to local ultraviolet radiation.

Local exposure of the sites of elicitation (ears) of contact hypersensitivity (CHS) in mice to relatively modest doses of ultraviolet radiation (FS40 sunlamps) daily for 4 days prior to challenge in previously immunized animals results in significant enhancement of the CHS response as measured by 24-h swelling. This effect was seen in both C3H/HeJ and A/J mice and with the use of both trinitrochlorobenzene and dinitrofluorobenzene as contact sensitizers. Doses of PUVA (parenteral administration of 8-methoxypsoralen followed by exposure to UVA, 320-400 nm, radiation) up to that which can systemically suppress the induction of CHS failed to affect the elicitation of CHS. Irritation of the sites of elicitation of CHS by applications of turpentine also failed to affect the CHS elicitation reaction. Enhancement of the CHS elicitation response by local ultraviolet radiation exposure prior to challenge appears to be a specific photobiologic event.

Animals↗
PubMed1986

In vivo inflammatory activity of epidermal cell-derived thymocyte activating factor and recombinant interleukin 1 in the mouse.

Epidermal cell-derived thymocyte activating factor (ETAF), a cytokine produced by keratinocytes, has previously been shown to be biochemically and functionally very similar, if not identical, to interleukin 1 (IL-1). Both ETAF and IL-1 have been demonstrated to be chemotactic for neutrophils and mononuclear cells in vitro. In order to demonstrate that this activity has physiological relevance we have used a simple in vivo model. The present study demonstrates that injection of high-titer ETAF or purified recombinant murine IL-1 into the mouse footpad results in an influx of neutrophils into the site with peak accumulation at 4 h. Footpad swelling also occurs with a time course roughly paralleling that of the neutrophil accumulation. Injection of control proteins failed to reproduce this phenomenon. Margination of neutrophils within blood vessels was seen within 1 h of injection of ETAF or IL-1, followed by entry into the stroma by 4 h. This suggests that chemotactic activity and not merely increased adherence or inhibition of migration is occurring. 5-10 d of daily, subcutaneous injection of ETAF on the mouse flank resulted in an infiltrate of neutrophils, and to a lesser degree, mononuclear cells in association with epidermal hyperplasia, subcutaneous fibrosis, and focal muscle necrosis in the panniculus carnosus. These findings were not seen in control sites injected with media. These findings provide direct in vivo experimental evidence suggesting a physiologic role for ETAF/IL-1 in local inflammation.

Animals↗
PubMed1985

Splenic I-J-bearing antigen-presenting cells in activation of suppression: further characterization.

A set of I-J-bearing murine splenic antigen-presenting cells (APC) has been found to be responsible for first order suppressor cell (Ts1, afferent suppressor cell) activation in the azobenzenearsonate (ABA) hapten system after intravenous administration. Suppressor cells induced by this set of hapten-coupled cells do not function in the efferent phase of the delayed hypersensitivity (DTH) response. The functional activity of this novel APC to activate afferent suppressor cells was resistant to a dose of ultraviolet radiation (UVR) sufficient to largely abrogate the ability of splenic APC to immunize for a DTH response. It was also found that the previously described splenic I-J-bearing APC needed for third-order suppressor cell (Ts3, effector-suppressor cell) activation is adherent and UVR resistant. The sets of I-J-bearing APC appear to be crucial elements in the activation of suppression and thus in determining the balance between immunologic reactivity and unresponsiveness. Furthermore, the UVR resistance of this set of novel APC may be relevant to the in vivo effects of UVR exposure to mice.

Animals↗
PubMed1985

Epidermal I-J-bearing cells are responsible for transferable suppressor cell generation after immunization of mice with ultraviolet radiation-treated epidermal cells.

Subcutaneous immunization of mice with hapten-coupled, ultraviolet radiation (UVR)-treated epidermal cells (EC) results in a hyporesponsive delayed-type hypersensitivity (DTH) response associated with the appearance of afferent-acting, hapten-specific T suppressor (Ts) cells. Depletion of I-J-bearing cells from the EC population prior to UVR-exposure and hapten coupling prevents the appearance of these Ts cells. However, non-UVR-treated EC depleted of I-J-bearing cells and hapten-coupled are capable of immunizing mice for a DTH response. Therefore, the set of I-J-bearing EC appears to be distinct from classic Langerhans cells. A novel set of I-J-bearing EC appears to be responsible for Ts activation after subcutaneous immunization with hapten-coupled UVR-treated EC.

Animals↗
PubMed1984

Immunologic inhibition of ultraviolet radiation-induced tumor suppressor cell activity.

Long-term exposure of C3H mice to ultraviolet radiation resulted in the formation of suppressor T cells that recognize ultraviolet radiation-induced regressor skin cancers as a class before the appearance of overt tumors. Administration of monoclonal antibodies to the product of the I-Jk subregion of the major histocompatibility complex or low doses of cyclophosphamide in vivo inhibited the development or activity of these cells. This activity of the monoclonal antibody was eliminated by adsorption on B10.BR (I-Jk) but not B10.D2 (I-Jd) splenocytes. These findings provide evidence that elements expressing the I-J determinant are important in regulating the host response prior to the overt development of ultraviolet radiation-induced skin cancers and suggest novel therapeutic approaches to malignancies or other diseases involving suppressor T cells in their pathogenesis.

Animals↗
PubMed1984

Suppressor T cells and the immune response to tumors.

In this paper we have attempted to define the role of suppressor T cells in many well-defined murine tumor systems. We have knowingly omitted a blocking antibodies, suppressor B cells as mediators of tumor immunosuppression in various murine tumor systems; these have been well reviewed elsewhere. Also, we have focused on the importance of two different types of antigen-presenting cells in the induction and suppression of cell-mediated immunity and on some of the different modalities employed to inhibit Ts function. Finally, we have discussed the acquired immunodeficiency syndrome and the possible role of a defective helper pathway and enhanced suppressor pathway in its pathogenesis. We and others believe that the suppressor pathway is preferentially activated by tumor antigen(s) in the cases of many immunogenic murine tumors--possibly due to the release of tumor antigen(s) from tumor cells, their subsequent trafficking to specific areas of the spleen and other organs, and, ultimately, their presentation by certain APC to Ts. Ts may then act directly upon helper Lyt 1+2- T cells as these cells interact with tumor antigen(s) on I-A+ APC. Alternatively, if the effector pathway were somehow impaired--e.g., by ultraviolet radiation or a virus--then the suppressor pathway may be activated in an unregulated manner, often to the detriment of the host. Biochemical characterization of the tumor antigens that stimulate Ts generation and, presumably, tumor growth and definitive documentation of a role of APC in the processing and presentation of these tumor antigens to Ts need to be done. Then selective stimulation of the effector immune response, along with inhibition of the suppressor response, to tumor antigens with drugs, monoclonal antibodies, and soluble mediators or their analogues may be possible in the near future.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Differential antigen presentation in tumor immunity.

The tumor S1509a elicits a cell-mediated immune response in immune A/J mice but leads to the generation of suppressor T cells (Ts) in nonimmune mice. Previous studies have shown that I-A+ antigen-presenting cells (APC) present S1509a tumor antigen and thereby activate immune T cells. Recent studies with polyoma-induced tumors reveal similar findings. Administration of anti-I-A antibodies not only prevents effective T cell activation by I-A+ APC bearing S1509a tumor antigen but also induces Ts after a tumor challenge. Ts, which inhibit S1509a tumor immunity, may be activated by tumor antigen presented on I-J+ APC. Examination of the immunologic effects of cyclophosphamide and UV radiation supports this hypothesis.

Animals↗
PubMed1984

Molecular signals in antigen presentation. II. Activation of cytolytic cells in vitro after ultraviolet radiation or combined gamma and ultraviolet radiation treatment of antigen-presenting cells.

Murine low-density spleen cells have potent antigen-presenting ability in a hapten-specific cytolytic T lymphocyte (CTL) system using the hapten azobenzenearsonate (ABA). Exposure of these cells to 0.33 KJ/m2 of ultraviolet radiation (UVR) after coupling to hapten results in markedly inhibited antigen-presenting function that can be substantially corrected or bypassed by interleukin 1 (IL 1). These results have been interpreted to reflect an inhibition of Lyt-1+ T cell activation by UVR-treated APC. Treatment of these cells sequentially with 1500 rad of gamma-radiation (GR) prior to hapten coupling, followed by 0.33 KJ/m2 of UVR radiation after coupling, results in an antigen-presenting defect only minimally improved by IL 1. However, partially purified interleukin 2 (IL 2) can completely bypass or correct this defect. Thus, combined GR and UVR induces a different or more profound defect in APC function when compared to UVR alone. However, these cells do provide a signal(s) other than hapten necessary for CTL activation because ABA-coupled high density spleen cells do not activate CTL cells, even with the addition of IL 2. Fluorescence-activated cell sorter analysis demonstrates that exposure of these low density spleen cells to GR or UVR results in decreased I-A antigen expression at 24 hr than either alone. The addition of nonhapten-coupled low-density APC partially reconstitutes the ability of combined GR/UVR-treated LD-APC to present antigen, and this effect is enhanced by the administration of exogenous IL 1. This occurs despite a lack of significant accessory cell activity by the LD-APC for the ABA hapten, and indicates that combined GR/UVR-treatment of APC is not functionally equivalent to completely removing them.

Animals↗
PubMed1983

Necrotizing vasculitis within cutaneous lesions of mycosis fungoides.

Mycosis fungoides is a T cell lymphoma with a predilection for cutaneous involvement. This paper describes the clinical manifestations and histopathologic features of a case of mycosis fungoides with necrotizing vasculitis localized to the lesions of cutaneous lymphoma. Elevated levels of circulating immune complexes were found in this patient. The large numbers of perivascular malignant helper T lymphocytes may have induced immunoglobulin synthesis, resulting in the formation of these complexes followed by deposition in vessel walls and subsequent necrotizing vasculitis. Possible alternative mechanisms include the presence of anti-T cell antibodies, or cytotoxic effector cells.

Adult↗
PubMed1983

The role of UVB radiation in the induction and elicitation of photocontact hypersensitivity to TCSA in the mouse.

Photocontact hypersensitivity (PHS) to 3,3',4',5 tetrachlorosalicylanilide (TCSA) can be induced in mice by using cyclophosphamide as an immunopotentiator. Only UVA (320-400 nm) radiation was required for both sensitization and elicitation of PHS. The reaction was successfully transferred to syngeneic mice by injecting them with lymph node cells from sensitized donors, a finding that demonstrates the immunologic nature of PHS. The presence of UVB (280-320 nm) radiation was not necessary for sensitization and did not increase PHS beyond the levels observed with UVA radiation alone. Ultraviolet radiation in the UVB range (plus a small amount of UVA radiation) from FS40 sunlamps in the dose employed did not induce statistically significant PHS to TCSA, nor did it elicit a significant response in mice sensitized with TCSA plus UVA radiation. However, treatment of mice with UVB radiation at a distant site 6 days before sensitization suppressed the induction of PHS. This suppression appeared to be analogous to the systemic suppression of ordinary contact hypersensitivity in mice by UVB radiation.

Adjuvants, Immunologic↗
PubMed1983

The role of suppressor cells in the induction of murine photoallergic contact dermatitis and in its suppression by prior UVB irradiation.

Induction in mice of marked photoallergic contact dermatitis (PCD) to 3,3',4',5-tetrachlorosalicylanilide (TCSA) with UVA (320 to 400 nm) radiation requires pretreatment with cyclophosphamide (CY). Attempts to induce photoallergic contact dermatitis without CY result in only a small degree of sensitivity, accompanied by significant net splenic suppressor cell activity. These suppressor cells are antigen specific, inhibit the induction but not the elicitation of photoallergic contact dermatitis to TCSA, and are T lymphocytes. Exposure of mice to UVB (280 to 320 nm) radiation at a site distant from that of sensitization, before CY administration and sensitization, inhibits the development of photoallergic contact dermatitis. This is analogous to the suppression of allergic contact dermatitis (ACD) observed in mice after exposure to UVB radiation; such suppression is accompanied by the formation of antigen-specific splenic suppressor cells. However, in contrast to the findings with allergic contact dermatitis, splenic suppressor cells are not detected in mice that are treated with UVB radiation before CY administration and sensitization to TCSA. This is presumably because CY prevents their formation. This provides evidence that UVB-irradiated mice have a second form of anergy that is not mediated by suppressor cells.

Animals↗