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R A Daynes

Publications and source records attributed to R A Daynes.

At least 73 records · Page 4Linked to original sources
PubMed1989

Relationship between inducible H-2 expression and the immunogenicity of murine skin neoplasms. I. Evidence that the immunogenicity of ultraviolet radiation-chemically induced tumors is associated with their susceptibility to gamma-interferon-mediated enhancement of H-2Kk expression.

Our objective was to determine the relationship between major histocompatibility complex class I molecule expression and the tumorigenic properties of cutaneous neoplasms induced by ultraviolet radiation or chemical carcinogens. All tumors tested were found to express low constitutive levels of MHC class I molecules in vitro as determined by indirect immunofluorescence and flow cytometry. Those tumors capable of growth in UVR-exposed but not in normal recipients (regressors) were found to express enhanced levels of H-2Kk following incubation in the presence of gamma-IFN. In contrast, only one of the tumors that were capable of growth in normal recipients (progressors) exhibited more than moderate enhancement of H-2Kk expression in response to gamma-IFN. Analysis of tumor variants obtained by conversion of a UVR-induced regressor tumor to the progressor phenotype by passage through sublethally gamma-irradiated hosts, or the generation of regressor tumors by mutagen exposure of a benz [A] pyrene (BAP) induced progressor tumor, further supported the direct relationship between tumor immunogenicity in vivo and the capacity to elevate H-2Kk expression in response to gamma-IFN. No correlation existed between H-2Dk expression by the tumors and their transplantation phenotype. Furthermore, we failed to observe MHC class II expression by any of the tumors tested. Finally, the growth rate of a regressor tumor implanted into UVR-exposed hosts was significantly reduced if the tumor was pretreated with gamma-IFN in vitro prior to inoculation. This result suggests that UVR-exposed animals may be deficient in their ability to enhance the expression of MHC class I molecules on developing tumors. This alteration may, in part, account for the state of tumor susceptibility caused by UVR exposure.

Animals↗
PubMed1988

Neuropeptide regulation of inflammatory and immunologic responses. The capacity of alpha-melanocyte-stimulating hormone to inhibit tumor necrosis factor and IL-1-inducible biologic responses.

Administration of the pituitary hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to mice was found to inhibit a number of IL-1 and TNF-inducible biologic responses in situ. The ability of either IL-1 or TNF to cause fever, enhance plasma levels of acute phase proteins, and increase the numbers of peripheral blood neutrophils was inhibited by the simultaneous peripheral administration of this neuropeptide. In addition, alpha-MSH reversed the depressive influences of IL-1 or TNF on the effector phase of contact hypersensitivity (CH) responses in animals given an adoptive transfer of primed lymphocytes from hapten-sensitized donors. Intracerebral injection of nanogram quantities of alpha-MSH inhibited the ability of peripherally administered IL-1 or TNF to induce both fever and neutrophilia without affecting the increase in plasma levels of serum amyloid P and fibrinogen. Also, nanogram quantities of alpha-MSH given intracerebrally to normal mice did not reverse the depressed CH responses observed after peripheral IL-1 or TNF administration. These findings suggest that both fever and neutrophilia are linked to the direct action of IL-1 or TNF on the brain. This was supported by the observation that an intracerebral injection of IL-1 or TNF in low doses increased core body temperature and circulating neutrophil numbers without affecting plasma levels of acute phase proteins or CH responsiveness. Our results provide additional support for the hypothesis that bidirectional control exists between elements of the neuroendocrine and immune systems.

Animals↗
PubMed1988

Membrane-associated NAD+ glycohydrolase from rabbit erythrocytes is solubilized by phosphatidylinositol-specific phospholipase C.

NAD+ glycohydrolase (NADase) present on the surface of rabbit erythrocytes is a membrane-bound ectoenzyme that can be solubilized by phosphatidylinositol-specific phospholipase C (PIPLC). As much as 70% of the cell-associated NADase was made soluble by treatment with PIPLC. The portion of NADase that remained cell-associated after an initial PIPLC treatment proved to be resistant to subsequent solubilization attempts. Further analysis showed that release of NADase from erythrocytes could not be attributed to the action of proteinases or phospholipase C. Erythrocytes obtained from other mammals were analyzed and found to have variable amounts of PIPLC-susceptible NADase. Practically, this finding can be used to easily solubilize membrane-bound NADase as a first step in its purification.

Animals↗
PubMed1988

Effect of ionizing radiation on thymic epithelial cell function. I. Radiation-spared thymic epithelial grafts expedite the recovery of T cell function in lethally irradiated and fetal liver reconstituted mice.

A murine model system was developed to determine whether ionizing radiation has a detrimental influence on thymic epithelium, cell function. Normal mice were lethally irradiated, grafted intracamerally with normal fetal thymic epithelium, and then reconstituted with fetal liver cells. These animals were compared with a group of animals who received their thymic grafts before the irradiation protocol. Analysis of the reconstitution of T cell function in peripheral lymph nodes and spleens at various times post transplantation demonstrated that animals with radiation-spared thymic grafts had superior proliferative responses to T cell mitogens and alloantigens. It was also determined that the capacity of these animals to elicit contact hypersensitivity responses was significantly greater when compared with animals whose thymic grafts had been radiated. The observed difference in T cell function could not be ascribed to a difference in the rate of export of mature T cells from the thymic grafts since the absolute number of Thy-1+, L3T4+, or Lyt-2+ lymphocytes present in the peripheral lymphoid compartment of our two groups of animals was equivalent. Immunohistologic analysis of the thymic grafts demonstrated a marked reduction in the medullary compartment of the repopulated grafts that had been exposed to ionizing radiation. The results of this study suggest: 1) that irradiation of the thymic microenvironment during marrow ablative preparative regimens may be in part responsible for some of the immune alterations observed in marrow transplant recipients, and 2) that our model system may provide a valuable tool for delineating the roles played by medullary and cortical epithelial cells of the thymus on the T cell maturation and education processes.

Animals↗
PubMed1988

Parallel recovery of epidermal antigen-presenting cell activity and contact hypersensitivity responses in mice exposed to ultraviolet irradiation: the role of a prostaglandin-dependent mechanism.

Contact hypersensitivity (CH) responsiveness to 2-4-dinitro-1-fluorobenzene (DNFB) is depressed in mice that are sensitized through skin sites exposed to ultraviolet radiation (UVR). This is partially due to a reduction in antigen-presenting cell (APC) activity within UVR-exposed skin, a condition marked by a decrease in the density of ATPase/Ia-positive epidermal cells. The purpose of this study was to correlate the histological and functional recovery of APC activity in the skin of C3H mice exposed to low-dose (4 X 450 J/m2) or high-dose (1 X 15 kJ/m2) UVR with the normalization of CH responsiveness. Skin biopsy specimens taken at various intervals after UVR exposure revealed a rapid recovery in the density of ATPase/Ia positive cells: about 70% of normal by 3 days, and normal after 5 days. Functional analyses showed that lymph node cells obtained from donors that were sensitized with DNFB 3 days after UVR treatment transferred normal ear-swelling responsiveness to non-primed recipients, thus indicating that APC activity in UVR-exposed skin paralleled the recovery of ATPase/Ia-positive epidermal cells. This suggested that an alternative mechanism causes the persistent depression of CH in mice exposed to UVR. Mice pretreated with indomethacin prior to UVR exposure demonstrated a capacity to elicit CH responses to DNFB, which paralleled the histological and functional recovery of APC in the skin (i.e., normal CH responses were elicited 3 days after exposure to UVR). We conclude from this study that APC activity in the skin recovers rapidly after exposure to UVR, and that a PG-dependent mechanism is responsible for many of the persistent and systemic effects that cause a depression in the CH responsiveness of mice treated with UVR.

Adenosine Triphosphatases↗
PubMed1987

Alpha-melanocyte-stimulating hormone exhibits target cell selectivity in its capacity to affect interleukin 1-inducible responses in vivo and in vitro.

The ability of i.v.-administered recombinant human interleukin 1 (IL 1 beta) to increase core body temperature, stimulate an increased production of serum amyloid P substance, and augment blood levels of circulating neutrophils in mice was inhibited in a dosage-dependent manner by administration of the neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH). alpha-MSH administration was also capable of inhibiting the capacity of i.v.-administered IL 1 beta to enhance plasma levels of corticosterone and to depress the generation and/or elicitation of contact hypersensitivity responses to skin-reactive chemicals. An analog of alpha-MSH (Nle4, D-Phe7 alpha-MSH), known to be more potent than native alpha-MSH in a number of melanotropin-sensitive systems, was determined to be more active than alpha-MSH in the modification of these same in vivo responses. Neither alpha-MSH nor its analog were capable of altering the capacity of IL 1 to stimulate increased plasma levels in prostaglandin E2 (PGE2). In vitro, neither alpha-MSH nor its analog were capable of reducing the capacity of IL 1 to stimulate fibroblast production of PGE2 or to augment the proliferation of murine thymocytes exposed to phytohemagglutinin. The apparent selectivity associated with the regulatory influences of alpha-MSH on IL 1-induced responses in vivo suggests that this neuropeptide may function as an endogenous inhibitor of certain immunomodulatory and inflammatory activities of the cytokine IL 1.

Animals↗
PubMed1987

Ability of cyclosporine to promote the growth of transplanted ultraviolet radiation-induced tumors in mice.

The use of immunosuppressive agents (primarily azathioprine and prednisone) to promote human allograft survival is known to be associated with an enhanced rate of skin cancer development by ultraviolet radiation (UVR). These observations raise the question of whether the immunosuppressive agents are functioning as cocarcinogen or whether they augment UVR-induced tumors by their successive influence on normal tumor-directed immune responses. In this report we have examined the effect of cyclosporine (CsA) on the capacity of murine UVR-induced tumors to grow following their transplantation to syngeneic recipients. We found that transplanted UVR tumors, selected for their inability to grow in normal recipients, were capable of progressive growth following implantation into CsA-treated recipients. This CsA-induced tumor-susceptible state could be reversed by treatment of prospective recipients with the drug cyclophosphamide (CY), supporting the concept that CsA was functioning in vivo by its capacity to promote suppressor cell generation. Further studies established that CsA treatment needed to be given at or near the time of tumor transplantation for susceptibility to occur. Our findings support the possibility that CsA is capable of promoting the survival and progression of UVR-induced skin tumors via its capacity to enhance the dominance of suppressor-cell-controlled immune responses.

Animals↗
PubMed1987

Murine responses to immunization with pertussis toxin and bovine serum albumin: I. Mortality observed after bovine albumin challenge is due to an anaphylactic reaction.

It has been suggested that pertussis toxin (Ptx) is involved in the pathogenesis of the adverse neurologic reactions that can occur in infants and children after pertussis immunization. One group of investigators has recently reported that a clinical syndrome with pathological features very similar to post-pertussis vaccination encephalopathy can be induced in specific strains of mice after their immunization with bovine serum albumin (BSA) and Ptx. The aim of this investigation was to further characterize the immunologic mechanisms operative in this murine model. Studies were undertaken to determine whether the role played by Ptx in this condition required the A-protomer of the toxin to enter a cell and ADP-ribosylate a nucleotide binding protein (a Class I activity) or was dependent upon the binding of the B-oligomer of the toxin to the surface of target cells (a Class II activity). The results of our experiments have established that the disease induced by coimmunizing mice with Ptx and BSA is due to an immediate type hypersensitivity reaction rather than an encephalopathy and that the mechanism of action of Ptx in this system seems to be dependent upon a Class II activity of the toxin and independent of its ADP-ribosyl transferase activity.

Adenosine Diphosphate Ribose↗
PubMed1987

Implantation of thymic epithelial grafts into the anterior chamber of the murine eye: an experimental model for analyzing T-cell ontogeny.

The object of this investigation was to establish whether the intracameral implantation of thymic epithelial grafts could be utilized as a valid in vivo experimental model for probing the possible mechanisms whereby the sympathetic innervation of the thymus influences thymocyte dynamics. Our findings suggest that deoxyguanosine-treated thymic epithelial grafts, implanted into the anterior chamber of the eye, were receptive to host lymphoid progenitor cells, capable of supporting T-lymphocyte maturational processes, and were able to export mature T cells to the secondary lymphoid organs of a previously T-cell deficient host. In addition, we verified that the number of lymphoid cells recovered from a thymic epithelial graft which had been implanted into an anterior chamber devoid of sympathetic nerve input was generally greater than the number of lymphoid cells recovered from a matched graft which had been implanted into an anterior chamber which had an intact sympathetic nerve supply. Based on the results of these studies, investigative efforts can now be directed at studying a number of important aspects associated with the relationship between T lymphocyte ontogeny and the sympathetic nervous system.

Animals↗
PubMed1987

Marrow ablative doses of gamma-irradiation and protracted changes in peripheral lymph node microvasculature of murine and human bone marrow transplant recipients.

Gamma-irradiation has been extensively utilized as a bone marrow ablative agent during human bone marrow transplantation. Although the effects of ionizing radiation on lymphoid and hematopoietic cells are well documented, little is currently known about its effect on the nonhematopoietic tissues which are important for the restoration of normal immune function. The vast majority of lymphocyte movement into peripheral lymph nodes takes place via the bloodstream and requires a specific receptor-ligand interaction between the lymphocyte and anatomically distinct postcapillary venules. Due to the importance of lymphocyte recirculation in the initiation and amplification of immune responses, an understanding of the radiosensitivity of the postcapillary venules may provide insight into the pathogenesis of the immune deficiencies commonly seen after bone marrow transplantation. Our studies disclosed that the ability of normal blood-borne lymphocytes to enter peripheral lymph nodes was markedly depressed (less than 50% of normal) in mice which had been exposed to 7.5 Gy of gamma-irradiation. This radiation-induced effect lasted longer than 6 months after irradiation and syngeneic reconstitution, and its magnitude was radiation-dose dependent. Immunochemical staining of the lymph node microvasculature with the monoclonal antibody MECA-325 established that the radiation protocol induced persistent anatomic changes in the lymphocyte-receptive areas of endothelium (high endothelial venules). These vessels developed the appearance of endothelial cell proliferation. Electron microscopy demonstrated significant intracellular edema, with virtual occlusion of many microvascular lumens by edematous endothelial cells. Lymph nodes from human bone marrow transplant recipients were found to exhibit similar ultrastructural changes. These studies for the first time demonstrate that doses of irradiation similar to those used to prepare bone marrow transplant recipients can have significant anatomic and functional sequellae on host endothelial cells.

Animals↗
PubMed1986

Alterations in lymphocyte recirculation within ultraviolet light-irradiated mice: efferent blockade of lymphocyte egress from peripheral lymph nodes.

Ultraviolet irradiation (uvR) has been demonstrated to have profound effects on many functions of the immune system. In particular, exposure to this physical agent can alter the tissue distribution and function of a number of immunologically active cell types, even at sites remote from direct uvR exposure. The present investigation demonstrates that uvR exposure of mice induces an efferent blockade of lymphocyte egress from the peripheral lymph nodes which drain the irradiated skin, resulting in marked retention of lymphocytes. In vivo studies of this efferent blockade established that the condition appeared similar in mechanism to that induced by the administration of poly-inosinic:poly-citidylic acid, murine interferon alpha/beta and specific antigen. We were able to establish that a common mechanism in the genesis of an efferent lymphatic blockade may involve prostaglandin biosynthesis. The potential contribution of efferent blockade to the development of systemic suppression of contact hypersensitivity induced by uvR exposure is discussed.

Animals↗
PubMed1986

Involvement of prostaglandins in the immune alterations caused by the exposure of mice to ultraviolet radiation.

Our study was designed to analyze the possible involvement of prostaglandins in the mechanisms responsible for the depressions in contact hypersensitivity (CH) responsiveness observed in UVR-exposed animals. Low-dose UVR-exposed animals were found to exhibit a depressed capacity to elicit CH responses after hapten application to irradiated (devoid of Langerhans cells) or UVR-protected (normal Langerhans cells) dorsal skin surfaces. Normal responsiveness was observed in low-dose UVR-exposed animals sensitized through unirradiated ventral skin surfaces. Indomethacin treatment of low-dose UVR-exposed animals (to inhibit prostaglandin synthesis in vivo) caused a retention in the capacity to respond normally to CH induction to haptens applied to the nonirradiated, but not to irradiated, dorsal skin surfaces. High-dose UVR-exposed animals, which normally exhibit a depression in responsiveness to hapten sensitization, retained a normal capacity to elicit CH responses if treated with the drug indomethacin. These findings implicate prostaglandins in the pathogenesis of the immunologic hyporesponsiveness, observed in low- and high-dose UVR-exposed animals. Our studies also determined that under all experimental conditions where animals were contact sensitized through nonirradiated skin sites, CH-effector cells could be found in the draining lymph nodes. No CH-effector cells were observed in the lymph nodes of mice that were contact sensitized directly through irradiated skin sites. It was also found that the spleens of both UVR-exposed and normal animals contained adoptively transferrable suppressor cells subsequent to hapten application. This demonstration of CH-effector and CH-suppressor cells in both normal and UVR-exposed animals did not directly relate to the potential of the donor animals to elicit a CH response.

Animals↗
PubMed1986

Desensitization of animals to the inflammatory effects of ultraviolet radiation is mediated through mechanisms which are distinct from those responsible for endotoxin tolerance.

The studies presented in this report indicate that the mechanisms responsible for both ultraviolet radiation (UVR)- and lipopolysaccharide (LPS)-induced desensitization are different from one another and appear to be regulated at the site(s) of administration of the inflammatory agent. Furthermore, desensitization to either UVR or LPS is not due to the inability of interleukin 1 (IL 1)-sensitive target cells within these animals to respond to this endogenous mediator of inflammation. These conclusions were based on the demonstrated ability of UVR-desensitized mice to undergo an acute-phase response after exposure to a systemically administered inflammatory agent (LPS). In a reciprocal manner, LPS-desensitized mice were found to elicit a normal acute-phase response after a single UVR exposure. In addition, both UVR- and LPS-desensitized mice were found to respond normally to the systemic administration of an exogenous source of semi-purified IL 1. Desensitization to the inflammatory properties of either UVR or LPS appears to be controlled at the site of interaction between the tissues capable of producing epidermal-derived thymocyte-activating factor (ETAF)/IL 1 (epidermal keratinocytes or reticuloendothelial cells, respectively) and the exogenous inflammatory stimulus. Peritoneal macrophages obtained from LPS-desensitized mice were found to have a markedly reduced capacity to secrete ETAF/IL 1 in vitro when compared to peritoneal exudate cells (PEC) obtained from normal mice. In parallel with this decreased secretory potential by PEC was the appearance of membrane-associated forms of this mediator. Membrane-associated IL 1 was not found to be present on PEC obtained from normal mice. Keratinocytes obtained from the skin of normal mice or keratinocytes isolated from the irradiated skin site of UVR-desensitized mice were both found to secrete high levels of ETAF/IL 1 constitutively in vitro. Furthermore, both sources of keratinocytes also expressed membrane-associated forms of ETAF/IL 1 constitutively. Therefore, unlike LPS desensitization, the phenomenon of UVR desensitization does not appear to induce changes in the ability of keratinocytes to secrete soluble forms or to express membrane forms of ETAF/IL 1. UVR desensitization may be a result of the inability of ETAF/IL 1 generated within the skin to reach the various IL 1-responsive target cells throughout the body, or may result from the impaired ability of UVR to stimulate ETAF/IL 1 production due to changes in the structure of the skin of chronically UVR-exposed animals.

Animals↗
PubMed1986

Cell-mediated immune responses to syngeneic tumors. I. Identification of two distinct CTL effector pathways which differ in antigen specificity, genetic regulation, and cell surface phenotype.

It has been demonstrated previously that draining lymph nodes (DLN) from tumor-immunized mice contain a population of lymphoid cells that are capable of differentiating into functional antitumor cytotoxic T lymphocytes (CTL) during in vitro culture. In the present studies, it was observed that DLN cells from either C57BL/10 (B10) or C3H mice that had been footpad-immunized with syngeneic tumor cells differentiated into CTL during a 4-day in vitro culture in the absence of added antigen. The specificity patterns of the CTL thus generated, however, were quite different in the two strains. DLN from B10 mice immunized with ultraviolet light-induced fibrosarcoma cells of B10 origin differentiated into CTL which were only capable of lysing target cells from the tumor used for immunization. Thus, the antitumor CTL which differentiate from B10 DLN appeared to be specific for the tumor-specific antigen (TSA) expressed by these tumor cells. In contrast, DLN from C3H mice immunized with a syngeneic ultraviolet light-induced fibrosarcoma differentiated into CTL which effectively lysed not only target cells from the immunizing tumor, but several other fibrosarcomas of both B10 and C3H origin, and which did not lyse normal nontumor targets. These C3H effectors thus appeared to be specific for a tumor-associated antigen (TAA) which is widely shared by a number of tumors. Cold target-blocking studies demonstrated that the CTL generated by C3H DLN cells contained a subpopulation of TSA-specific cells in addition to cross-reactive TAA-specific effectors. (B6 X C3H)F1 (B6C3F1) mice generated cross-reactive TAA-specific CTL in response to in vivo challenge with either B10 or C3H tumors, indicating that the ability to generate a TAA-specific CTL response behaves as a dominant trait of the responding mouse strain and not as a function of the tumor used for immunization. TSA-specific CTL and cross-reactive TAA-specific CTL were distinguishable on the basis of their cell surface phenotypes, because the TSA-specific CTL generated by B10 DLN cells were Thy-1.2+ Lyt-2.2+, whereas TAA-specific B6C3F1 CTL were Thy-1.2+ Lyt-2.2-; alloantigen-specific CTL generated from the same B6C3F1 lymph nodes were Thy-1.2+ Lyt-2.2+.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Neuropeptide regulation of interleukin-1 activities. Capacity of alpha-melanocyte stimulating hormone to inhibit interleukin-1-inducible responses in vivo and in vitro exhibits target cell selectivity.

alpha-Melanocyte stimulating hormone (alpha-MSH), a 13 amino acid neuropeptide produced by the pituitary gland, was found to markedly inhibit the capacity of exogenously administered interleukin-1 (IL-1) to stimulate the enhanced synthesis of acute-phase proteins and induce neutrophilia in vivo. The administration of ACTH or glucocorticosteroids lacked most of these direct IL-1 inhibitory properties. Therefore, in addition to the previously reported antipyretic action of alpha-MSH, this hormone can also inhibit two other known IL-1 sensitive cellular targets in vivo. Further, alpha-MSH was incapable of modifying the comitogenic influence of IL-1 on murine thymocytes or on an IL-1 responsive T-cell line. These findings suggest a target cell specificity to the IL-1 inhibitory activities of alpha-MSH and fail to support the hypothesis that alpha-MSH functions through competitive inhibition of specific cellular receptors for IL-1.

Adrenocorticotropic Hormone↗
PubMed1986

Modification of the murine immune system by glucocorticosteroids: alterations of the tissue localization properties of circulating lymphocytes.

Glucocorticosteroids have proven capable of suppressing both developing and ongoing immune responses via mechanisms that are not fully understood. Most investigations into the mechanisms of glucocorticosteroid-mediated immunosuppression have examined the direct effects of these agents on the lymphocyte itself. In this paper, we have analyzed the effects of glucocorticosteroids on the lymphocyte receptive capacity of lymph nodes and bone marrow in mice. These effects appear to be mediated via reversible changes in the capacity of steroid-treated vascular endothelial cells to interact with normal lymphocytes, and are both dose and time dependent. The most striking effects on lymphocyte localization were observed in mice given microgram quantities of glucocorticosteroids over a 6-day period via a continual release pellet. The direct exposure of lymphocytes to these drugs in vitro was shown to have no effect on their subsequent localization potential in vivo. Further studies revealed that the ability of antigen-sensitized effector lymphocytes to localize into sites of antigen deposition was also markedly depressed in mice pretreated with glucocorticosteroids. Therefore, steroids also appear to have effects on tissue associated endothelial cells which prevent the localization of sensitized effector lymphocytes into sites of active inflammation. Our observations have potential clinical implications, both in understanding the anti-inflammatory effects of glucocorticosteroids more fully, as well as suggesting that low-dose continual-release steroid administration may result in enhanced immunosuppression.

Animals↗