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Biomedical subjects

G E Kelly

Publications and source records attributed to G E Kelly.

At least 37 records · Page 2Linked to original sources
PubMed1987

Effects of therapy with azathioprine and prednisolone and ultraviolet irradiation on mouse skin immune function and immune cell markers.

The effects of ultraviolet irradiation (UVI) (290-400 nm) and/or systemic immunosuppressive drug therapy (azathioprine and prednisolone) on the immunocompetence of the skin of hairless (HRA/Skh-1) mice were investigated. Mice were studied for the density of ATPase+, Ia+ and Thyl X 2+ cells in the dorsal epidermis and contact hypersensitivity (CH) of skin to dinitrofluorobenzene (DNFB). Prednisolone therapy alone and UVI alone each reduced the densities of the three skin immune cell markers and CH responsiveness; azathioprine therapy alone had no such effects. When a suberythemal dose of UVI that induced a moderately depressive effect on these two skin parameters was used, additional azathioprine therapy produced no further depression; additional prednisolone therapy further depressed the densities of ATPase+ and Ia+ cells and CH responsiveness; additional therapy with combined azathioprine and prednisolone induced profound depression of the incidences of the three immune cell markers and of CH responsiveness. These data point to interaction between azathioprine/prednisolone therapy and UVI in depressing local immune function within skin which may contribute to the increased susceptibility of the sun-exposed skin of immunosuppressed kidney transplant recipients to infective and carcinogenic processes.

Adenosine Triphosphatases↗
PubMed1987

Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice.

The effects of therapy with four commonly used immunosuppressants--azathioprine, prednisolone, cyclophosphamide, and cyclosporine, on (UVI)-induced skin carcinogenesis were studied in the albino hairless (HRA/Skh-1) mouse. Following 30 weeks' exposure to UVI (290-400 nm) alone, 87% of mice developed skin tumors; the mean incidence of tumors at that time was 2.4 per mouse; and the tumors were predominantly papillomas (72%), with the remainder being carcinomas (25%) and keratoacanthomas (3%). Mice received immunosuppressive drug therapy beginning shortly after the start of UVI and continuing for up to 28 weeks. All drugs were given at immunosuppressive levels and dosages were comparable on a body weight basis to those used in clinical transplantation. Prednisolone had no effect on UVI-induced tumor development. Cyclosporine caused a moderate reduction in the latent period for tumor induction. Azathioprine and cyclophosphamide had strong promoting effects; the latent period for tumor induction was shortened and the tumor yield per mouse was increased (4.3 and 5.7 tumors per mouse, respectively, at 30 weeks after the start of UVI). Azathioprine, but not cyclophosphamide, also induced a larger proportion of carcinomas (43% and 15%, respectively). The results suggest that for kidney transplant recipients treated with the standard immunosuppressive drug regimen of azathioprine/prednisone, the increased susceptibility of the sun-exposed skin of these patients to squamous cell carcinoma is likely to be contributed to by specific promotion by the azathioprine therapy of the carcinogenic effects of sunlight.

Animals↗
PubMed1987

Scheduled and unscheduled DNA synthesis in epidermal cells of hairless mice treated with immunosuppressive drugs and UVB-UVA irradiation.

The effects of the immunosuppressive drugs azathioprine, prednisolone and cyclosporin A, and UV irradiation on scheduled DNA synthesis, representing mitotic activity, and unscheduled DNA synthesis, representing DNA repair activity, in the skin of hairless mice were determined autoradiographically following intradermal administration of [3H]-thymidine. Azathioprine and prednisolone, and, to a lesser extent, cyclosporin A, were found to impair normal repair of UVR-induced DNA lesions in epidermal keratinocytes. Prednisolone, but not the other two drugs, further suppressed the normal delayed mitotic response in the skin following UVR. The depressive effects of these drugs, particularly the combined azathioprine/prednisolone regime, on scheduled and unscheduled DNA synthesis are considered likely to predispose skin to mutagenic and carcinogenic processes.

Animals↗
PubMed1986

Effects of ultraviolet radiation and immunosuppressive therapy on mouse epidermal cell kinetics.

The effects of immunosuppressive drugs on epidermal cell mitotic activity and the proliferative response of epidermis following ultraviolet radiation (UVR) were tested. Hairless (Skh-hr 1) mice were treated with immunosuppressive drugs at equivalent clinical doses with or without concomitant UVR (290-400 nm). Epidermal parameters measured were mitotic index (Im), rate of entry into mitosis (Fm), flash labelling index (FLI), rate of entry into DNA synthesis (Fs) and DNA content (flow cytometric analysis). In non-irradiated skin, prednisolone therapy depressed both mitotic activity and DNA synthesis; azathioprine and cyclosporin A had no effect; cyclophosphamide therapy increased the Fm and FLI values. Following repeated doses of UVR, there were enhanced mitotic activity and DNA synthesis in epidermis. Prednisolone therapy moderately depressed both proliferative responses; cyclophosphamide enhanced mitotic activity; azathioprine and cyclosporin A had no effect on these responses. The significance of these findings in relation to potential for increased susceptibility of skin to UV-induced carcinogenesis is discussed.

Animals↗
PubMed1986

Treatment of acute rejection episodes in dog renal allograft recipients receiving cyclosporin A:ATG vs prednisolone.

Prednisolone and antithymocyte globulin (ATG) were compared for their abilities to reverse acute rejection in cyclosporin A-treated canine graft recipients. Outbred dogs bearing kidney allografts were treated with a suboptimal dose of cyclosporin A (10 mg kg-1); at the onset of an acute rejection episode, animals received daily prednisolone (40 mg kg-1) or ATG (20 mg kg-1) until serum creatinine levels decreased. In seven untreated allograft recipients, rejection was first diagnosed at a mean 4.4 days post-transplant. In 23 dogs receiving cyclosporin A, rejection was first diagnosed in all dogs at a mean 43.6 days post-transplant. Compared to ATG, prednisolone was more successful in the reversal of primary acute rejection episodes (5/8 and 7/8 reversals, respectively) and produced a quicker return to normal renal function (mean 15.4 and 6.8 days, respectively). ATG therapy, however, resulted in fewer subsequent acute rejection episodes than prednisolone therapy (mean 1/5 and 6/7 developed secondary rejection episodes, respectively); the possible advantage of 'clonal depletion' following ATG therapy is discussed.

Acute Disease↗
PubMed1984

Nonspecific immunological studies in kidney transplant recipients with and without skin cancer.

The immunocompetence of the following patient groups was compared using peripheral blood mononuclear cells in a variety of in vitro assays: controls (84); hemodialysis patients (32); kidney transplant recipients without cancer (172), and those with skin cancer (18). The in vitro functions assayed were blastogenic responsiveness to phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen, allogeneic lymphocytes, and two cocktails of bacterial, viral, and fungal antigens; cytotoxic functions assayed were spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Compared with control subjects, hemodialysis patients showed depressed responsiveness to one antigen cocktail only. Transplant patients with no cancer showed uniformly depressed responsiveness to PHA and allogeneic lymphocytes and reduced SCMC and ADCC activity up to 12 years after transplant; responsiveness in these patients to the two antigen cocktails, after initial depression, recovered by 3 years after transplant to exceed control values. The group of 18 transplant recipients with skin cancer, when compared with transplant recipients with no cancer at a comparable period after transplant, showed similar depression of SCMC and ADCC activity, but significantly greater depression of responsiveness to PHA (P less than 0.01), allogeneic lymphocytes (P less than 0.05), and the 2 antigen cocktails (P less than 0.05).

Antibody Formation↗
PubMed1983

Sister chromatid exchange in lymphocytes from renal transplant recipients with and without cancer.

The frequency of sister chromatid exchange (SCE) was measured in peripheral blood lymphocytes from control, healthy subjects and immunosuppressed recipients of cadaveric donor kidneys with and without skin cancer. The mean SCE frequency in 43 control subjects was 9.2 per cell (range 5.4-12.3). In 30 transplant recipients with no history or evidence of cancer the mean SCE rate was 10.3 per cell (range 5.8-24.5); four (13%) of these patients had a mean SCE frequency outside the control range. In 7 transplant recipients with skin cancer, the mean SCE frequency was 14.3 per cell (range 9.1-19.9). This was significantly (P less than 0.01) higher than the mean value of control subjects. The mean SCE frequencies in 3 of these 7 patients fell within the control range and in 4 of these patients was above the control range. These results suggest that some immunosuppressed kidney transplant recipients are liable to chromosomal damage.

Azathioprine↗
PubMed1982

Reliability of the thermodilution method in the determination of cardiac output in clinical practice.

The thermodilution (TD) method of determining cardiac output (CO) is widely used in clinical practice, but its reliability in this setting is not well understood and may be poor. This is especially true when dealing with unstable patients and using commercial TD devices. Numerous published reports have shown markedly variable results when comparing simultaneously the TD method and the Fick or dye-dilution methods in catheterization laboratories, intensive care units, or operating rooms. In order to assist clinicians in interpreting the reliability of the TD method in measuring CO, we analyzed all available published data (14 reports). The differing results in these reports were evaluated by standard statistical methods and by an extension of the influence function method of structural analysis developed to differentiate reproducibility and accuracy errors of each technique. Comparing the accuracy of the TD method with that of the Fick or the dye-dilution methods reveals that the 3 methods are of equal merit and can be used as independent references. Our reproducibility data show that when using commercial TD devices there must be a minimal difference of 12 to 15% (average, 13%) between determinations of cardiac output (3 measurements per determination) to suggest clinical significance. Minimal differences of 20 to 26% (average, 22%) are required between determinations when using 1 measurement per determination. There was no difference in the quality of the TD method when comparing rapid injection of iced or room temperature thermal indicator.

Cardiac Output↗
PubMed1980

Studies of surface markers on canine lymphocytes.

Canine lymphoid cell preparations from blood, lymph node, spleen, thoracic-duct lymph and thymus were examined for the presence of such surface markers as surface immunoglobulin, thymic-specific antigen, Fc receptor and E-rosette formation with normal (E) and neuraminidase-treated (EN) human red blood cells. E-RFC and EN-RFC were further isolated and tested for reactivity in mixed lymphocyte culture.

Animals↗
PubMed1979

Cancer following renal transplantation.

Ninety-nine (21%) of 471 patients who survived with functioning grafts for at least six months following renal transplantation developed cancer. Of these 76 (77%) had skin malignancy, 29 (29%) had malignancy affecting other organs, and six had cancer of both skin and other organs. In patients with skin cancer squamous cell carcinoma (SCC) was three times as frequent as basal cell carcinoma (BCC). SCC tended to be multiple, recurrent and aggressive. Seven (12%) patients with SCC developed metastases of whom five died. Cancers other than skin included reticulum cell sarcoma (9), acute leukaemia (2) and cancers involving the gastrointestinal (5), genitourinary (11) and respiratory (2) systems. Incidence of cancer in patients surviving beyond one, five and nine years after operation was 98/428 (23%), 70/179 (39%) and 20/45 (44%) respectively. In 31 patients who died more than five years after transplantation cancer was the major cause in eight (26%). For the types of cancers recorded estimates show allograft recipients to be at increased risk when compared with the age-matched Australian population by factors which varied from 300 times for reticulum cell sarcoma to 1.8 times for invasive carcinoma of the cervix. The full extent of the threat of cancer in immune suppressed transplant recipients remains to be determined.

Adolescent↗
PubMed1977

Morphological differences between sub-populations of human lymphocytes revealed by scanning electron microscopy.

Human lymphoid cells were examined by scanning electron microscopy (SEM) to see if a correlation existed between surface morphologic features and the presence of various surface markers and receptors. When viewed by SEM thymocytes appeared as smooth-surfaced cells with few surface microvilli; peripheral blood lymphocytes (PBL) on the other hand were moderately to densely villate with no entirely smooth-surfaced cells observed. Surface morphology within PBL samples was not uniform, due mainly to variations in the shape and number of microvilli. However, 2 distinctive types of surface morphology (termed Types 1 and 2) were discernable with a small number of cells displaying features of both groups (Type 3). The majority of E-rosette forming cells (T lymphocytes) displayed Type 1 and the majority of cells bearing demonstrable surface immunoglobulin (B lymphocytes) displayed Type 2 morphology. Exposure of PBL to anti-T cell specific ALG resulted in cytolysis of cells with Type 1 morphology while cells with Type 2 morphology appeared largely unaffected. PBL with Fc and C3 receptors displayed all 3 types of morphology. It is concluded that T and B lymphocytes do have subtle but nevertheless discernable differences in surface morphology and within these 2 groups, variations in surface morphology are probably associated with changes in the physiological status of the cell.

Cell Membrane↗
PubMed1977

Current prospects for renal transplantation in veterinary practice.

In dogs, the surgical techniques and other technical considerations for the transplantation of most tissues and organs in the body are well established. The last remaining obstacle to uniformly safe and successful organ transplantation is the immune response to foreign tissue antigen and our present inability to completely suppress this response in a specific and safe manner. Immunosuppressive techniques currently available are largely non-specific and unfortunately cause many potentially fatal side effects. As a result graft recipients must be constantly monitored so that enough immunosuppressive treatment is given to prevent rejection but not so much that the recipient develops life threatening complications. The enormous cost and the services necessary to provide this attention in view of the relatively poor survival rates of tissue and organ grafts in dogs will continue to prevent organ transplantation becoming a reality in veterinary practice. Hopefully future advances in tissue-typing and the induction of specific immunological adaption in dogs by ensuring consistently safe and successful transplantation will ead to minimal postoperative attention.

Animals↗
PubMed1977

E-rosette forming cell numbers in the blood of human renal allograft recipients.

The incidence of circulating T lymphocytes (ET-RFC) and a sub-population of T lymphocytes (EE-RFC) were monitored in the blood of seventy-one cadaver renal allograft recipients for the first 2 months after transplantation. In patients with uneventful post-operative courses, the incidence of both ET-RFC and EE-RFC fell promptly upon initiation of immunosuppression returning approximately to pre-operative levels 3-5 weeks after operation; the fall in cell numbers was greatest in those patients receiving adjunct ALG therapy. With the onset of an acute rejection episode, the EE-RFC level rose quickly eventually exceeding the pre-operative level; in 88% (thirty episodes) of cases this rise occurred 1-6 days before clinical diagnosis of rejection and in 12% of cases on the same day as clinical diagnosis. The incidence of ET-RFC rose in conjunction with some cases of acute rejection but remained unchanged in other cases. It is suggested that measurement of the incidence of EE-RFC in blood is valuable in predicting the onset of acute rejection and for the differential diagnosis of acute rejection and ischaemic renal damage.

Creatinine↗