Search PubMed⌕ Search

Biomedical subjects

R M Ferguson

Publications and source records attributed to R M Ferguson.

At least 181 records · Page 10Linked to original sources
PubMed1983

Morphology of cyclosporine nephrotoxicity and acute rejection in patients immunosuppressed with cyclosporine and prednisone.

Cyclosporine nephrotoxicity is a common and usually reversible cause of renal insufficiency in the renal allograft recipient. We examined 132 renal biopsy specimens of 54 patients with elevated serum creatinine concentrations in the posttransplant period in an attempt to characterize histologic features that would identify patients with cyclosporine nephrotoxicity as opposed to those with acute rejection. Nine histologic parameters were examined--vasculitis, interstitial edema, distribution and intensity of mononuclear cell interstitial infiltrate, mononuclear cell exudation within glomerular capillaries ("glomerulitis"), tubular ectasia, tubular necrosis, exudation of mononuclear cells within tubular epithelial cells ("tubulitis"), and the ratio of mononuclear cells in interstitial tissues and in the peritubular capillaries (I/C ratio). A clinical response to an increased dose of steroids or a reduced dose of cyclosporine was correlated with the histologic picture. Tubulo-interstitial nephritis was identified in all but one patient with cyclosporine nephrotoxicity and only the finding of vasculitis allowed the identification of rejection with any certainly. However, the linear logistic regression method identified four histologic parameters--vasculitis, edema, glomerulitis, and I/C ratio, which were useful in differentiating the nephritis of cyclosporine nephrotoxicity from that of acute rejection in 94% of the biopsies. Although it is possible to precisely predict clinical response to antirejection therapy or reduction in cyclosporine dose based on histologic criteria, it is possible that cyclosporine toxicity, alone or in combination with rejection, may lead to chronic interstitial fibrosis responsible for late graft loss.

Animals↗
PubMed1982

Fractionated total lymphoid irradiation as preparative immunosuppression in high risk renal transplantation: clinical and immunological studies.

Twenty-two patients at high risk to reject renal allografts have been treated with fractionated total lymphoid irradiation (FTLI) prior to transplantation of primary (2), secondary (16) or teritary (4) renal allografts. All patients undergoing retransplantation had rapidly rejected previous grafts. At 24 months following transplantation, 72% of grafts were functioning in the TLI group compared with a 38% graft function in an historical control group of recipients receiving secondary or tertiary grafts and treated with conventional immunosuppression. Important variables in determining success of transplantation following fractionated TLI include the dose of TLI, the interval from radiation to transplantation, and maintenance, post-transplant immunosuppressive therapy. Optimal results were achieved with 2500 rads delivered in 100 rad fractions followed by transplantation within two weeks, and a tapering prednisone schedule and maintenance azathioprine post-transplantation. Seventeen patients had significant complications of the radiation treatment and there was one death, prior to transplantation, associated with pneumonitis. In vitro assessment of immune function demonstrated marked peripheral T cell depletion and loss of in vitro responsiveness to mitogen and allogeneic stimulation following FTLI. The administration of donor bone marrow at the time of transplantation did not produce chimerism. The results suggest that when properly utilized FTLI can produce effective adjunctive immunosuppression for clinical transplantation.

Adolescent↗
PubMed1982

Cyclosporin A for immunosuppression: observations in rat heart, pancreas, and islet allograft models and in human renal and pancreas transplantation.

Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.

Adolescent↗
PubMed1982

Analysis of cloned T cell function. I. Dissection of cloned T cell proliferative responses using cyclosporin A.

CsA interferes in a specific manner with the expansion of T cell clones in that it inhibits the antigen-driven component of the proliferative responses made by cloned helper T cells, cloned conventional cytolytic T cells, and cloned helper-independent cytolytic T cells. Cloned helper T cells and helper-independent cytolytic T cells, which share the ability to proliferate when cultured with specific alloantigen, fail to proliferate when cultured with specific alloantigen, fail to proliferate in response to this stimulus in the presence of CsA (10 to 100 ng/ml). In contrast, the proliferation observed when these cells are cultured with exogenous growth factors (but not alloantigen) is little influenced by as much as 1000 ng/ml CsA. When cloned helper T cells or helper-independent cytotoxic T cells are cultured with alloantigen plus exogenous growth factor, additive or synergistic proliferation occurs. However, CsA (10 to 1000 ng/ml) blocks only the component of proliferation induced by alloantigen, and leaves the lymphokine-driven component intact. CsA has similar effects on the proliferation of cloned conventional cytolytic T cells. Thus, CsA separates cloned T cell proliferation into two components: one driven by contact with alloantigens, the other driven by contact with mitogenic lymphokines.

Animals↗
PubMed1982

Cyclosporin A in renal transplantation: a prospective randomized trial.

Cyclosporin A combined with prednisone was compared with standard immunosuppressive therapy (antilymphoblast globulin, prednisone, and azathioprine) in a prospective randomized trial of 100 mismatched, living related donor and cadaveric renal transplants. The results demonstrated cyclosporin A plus prednisone to be an effective immunosuppressive regimen for renal transplantation. The actuarial graft survival at 1 year was 93% for patients treated with cyclosporin A and 81% for patients treated with conventional immunosuppression. Patient survival was 98% for the cyclosporin A group and 100% for the conventional group. Cyclosporin A-treated patients had fewer rejection episodes and fewer infections complications including a marked decrease in the incidence of posttransplant cytomegalovirus infection. The side effects of cyclosporin A were mild, but nephrotoxicity caused by cyclosporin A was frequent and significant. Nephrotoxicity was reversible and managed by decreasing the daily cyclosporin A dose. It is concluded that the combination of cyclosporin A plus prednisone provides an excellent alternate immunosuppressive regimen for renal transplants as compared with conventional therapy. The consequences of long-term administration of cyclosporin A are at present unknown.

Adolescent↗
PubMed1982

Immunotherapy of gram-negative bacterial sepsis: enhanced survival in a guinea pig model by use of rabbit antiserum to Escherichia coli J5.

A rough mutant of Escherichia coli (J5), which expresses a core lipopolysaccharide antigen common to gram-negative organisms on its cell surface, was used to immunize rabbits. Passively transferred anti-E. coli J5 rabbit antiserum (anti-J5 RS), normal rabbit serum (NRS), and saline were compared in a guinea pig model of intravenous gram-negative sepsis, with E. coli 0111:B4 and Pseudomonas aeruginosa as challenge organisms. Physiologic monitoring demonstrated a consistent pattern associated with gram-negative sepsis in this model: hypothermia, hypotension, bradycardia, a fall in white blood cell count and platelet count, and persistence of challenge organisms within the circulation. Pretreatment with anti-J5 RS prevented hypothermia and the fall in platelet count while augmenting bacterial clearance. Survival was markedly enhanced by anti-J5 RS, but not by NRS or saline. Concomitant heparin pretreatment was thought to be a significant factor in demonstrating the protective effect in this model. Parallel in vitro cross-reactivity measured by an enzyme-linked immunosorbent assay and an opsonization assay demonstrated that anti-J5 RS extensively cross-reacted with a variety of gram-negative bacilli. Demonstration of enhanced opsonization by anti-J5 RS of gram-negative organisms was thus well correlated with enhanced systemic clearance of bacteria and improved survival subsequent to intravenous bacterial challenge.

Animals↗
PubMed1981

Cimetidine reduction of tumour formation in mice.

Cimetidine, a histamine type-2 receptor antagonist, had a protective effect in mice challenged with cells from two different syngeneic tumours. The results are a further indication of cimetidine's potential as an immunostimulator.

Animals↗
PubMed1981

Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital.

During a three year period in which 433 renal transplants were performed, 194 episodes of fever were documented in allograft recipients hospitalized at the University of Minnesota. Viral infections were responsible for over half of the febrile episodes, and 98 (51 percent) of the fevers were associated with cytomegalovirus (CMV), either occurring alone or in conjunction with allograft rejection or another systemic infection. Bacterial infections, fungal infections and rejection were other important causes of fever, accounting for 14 percent, 5 percent and 13 percent of the febrile episodes, respectively. Most fevers occurred in the first four months after transplantation; although about two thirds of these fevers were due to CMV, only 17 percent of fevers that occurred more than one year after the renal transplant were due to CMV. Bacterial and fungal infections and malignancy were important causes of these fevers. Of the febrile illnesses associated with transplant nephrectomy or death, a majority occurred in patients with CMV disease. Secondary bacterial and/or fungal infections were observed in a large majority of patients with lethal CMV disease. During the third year of this study there was a significant decrease in the proportion of febrile episodes due to CMV.

Adolescent↗
PubMed1981

Cimetidine protection against lethal tumor challenge in mice.

Cimetidine, a histamine type-2 receptor antagonist, has been shown to augment proliferative responses of lymphocytes in man and mouse and to increase in vitro-generated murine cell-mediated cytotoxicity. It has been suggested by others that histamine receptors are involved in modulating the immune response through mediation of suppressor cell function. We have previously described a murine tumor model in which suppressor function increases with advancing tumor burden. We now have examined the in vivo effect of cimetidine on survival in this tumor-bearing murine model. Cimetidine was administered in the drinking water to C57BL/6 mice after an intraperitoneal injection of an LD90 dose of EL4 tumor cells. The survival rate was noticeably improved (56%) with an optimal dose of cimetidine (100 mg/kg/day) after 30 days, compared to that of water-treated control mice (10%). This protective effect was present with young (2 months old) as well as older (8 months old) mice. Rechallenge of cimetidine-treated survivors with a six times LD100 tumor dose and continuation of cimetidine produced a 33% survival rate. Comparison of cimetidine (100 mg/kg/day) with different doses of diphenhydramine (histamine type-1 antagonist) showed the protective effect to be more type-2 specific. The mechanism of action of cimetidine remains unclear, but based on this work and work by others, we think that cimetidine probably modulates suppressor cell function. Cimetidine may have potential as an immunomodulator.

Animals↗