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R M Ferguson

Publications and source records attributed to R M Ferguson.

At least 91 records · Page 5Linked to original sources
PubMed1993

Analysis of inflammatory endothelial changes, including VCAM-1 expression, in murine cardiac grafts.

We have employed a murine model of cardiac transplantation and two monoclonal antibodies, M/K-2 and MECA-32, to study the responses of graft endothelia during allograft rejection. Using immunohistologic techniques, we demonstrate that the monoclonal antibody M/K-2, which binds to the murine cellular adhesion molecule VCAM-1, reacts with an inducible endothelial epitope found in rejecting cardiac allografts, but not in cardiac isografts, normal cardiac tissues, or extracardiac vasculature from allografted mice. Similar, but focal, M/K-2 reactivity is also found in nontransplanted hearts undergoing virally induced myocarditis. M/K-2 reactivity does not develop in the nonrejecting cardiac allografts from nu/nu mice, and M/K-2 reactivity is found only in grafts that develop CD25+ graft-infiltrating cells--i.e., allografts but not isografts. PCR analyses of grafts during development of VCAM-1 expression indicate that allografts, but not isografts, contain mRNA for the cytokines IL-2 and IFN-gamma, and either of these cytokines may be associated with the expression of M/K-2 reactivity in rejecting allografts. Unlike M/K-2, MECA-32 identifies an inducible epitope that is observed on myocardial endothelia of both isografts and allografts, but not normal cardiac tissues. Further, expression of the MECA-32 epitope can occur in grafts that do not develop CD25+ infiltrating lymphocytes, since it is observed in isografts and the native hearts of transplanted or sham-operated mice. Indeed, MECA-32 reactivity may be T cell independent, since it is also found in nonrejecting allografts of nu/nu mice. PCR analyses of grafts during development of MECA-32 reactivity indicate that cardiac isografts contain mRNA for IL-1, IL-6, TNF, and lymphotoxin. One or more of these might be associated with induction of MECA-32 reactivity.

Animals↗
PubMed1993

A randomized, prospective, double-blinded trial of cyclosporine vs. OG37-325 in cadaveric renal transplantation--a preliminary report.

The efficacy of cyclosporine is documented, but it has side effects that are troublesome. Another compound, OG37-325, has been identified that appears to have similar efficacy, but less nephrotoxicity. This study was designed to address the benefits and toxicities of cyclosporine and OG37-325 in a prospective, randomized, double-blinded trial in cadaveric renal transplant recipients. The preliminary results demonstrate similar outcomes in terms of patient and graft survival, but suggest less nephrotoxicity in the OG37-325-treated patients. Longer follow-up will delineate the utility of OG37-325 in solid-organ transplantation.

Adult↗
PubMed1993

Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts.

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.

Animals↗
PubMed1993

OKT3 for primary therapy of the first rejection episode in kidney transplants.

The improvement in one-year graft survival has allowed transplant centers to focus on long-term graft survival. A study of 665 primary cadaveric kidney transplants from a single center treated with cyclosporine demonstrated that patients did not develop chronic rejection if there was not an episode of acute rejection. This study is a retrospective review of 314 consecutive kidney transplants from a single center to determine if early, aggressive treatment of the first episode of acute rejection will improve graft survival without increasing recipient morbidity. The course of 314 consecutive kidney transplants performed during a 27-month period (245 CAD and 68 living-related) was studied. Demographic characteristics were equivalent between the two groups, and all patients received sequential quadruple immunosuppression using ALG and CsA. Patient and graft survivals at 2 years were 89.7% and 84%, respectively. At least one rejection episode occurred in 41% of the patients, one-half within 30 days of transplant. Rejection episodes were treated by oral prednisone taper, primary ALG or OKT3, or "rescue" therapy with ALG or OKT3. Graft survival in the 52 recipients treated with OKT3 for primary treatment of first rejection episode was 20% better than the 50 patients treated with PRED (P = 0.0847). Comparing the 39 recipients of primary CAD kidneys treated with primary OKT3 vs. 38 treated with PRED demonstrated a 32% improvement in 2-year graft survival (P = 0.033). There was no increase in second rejection episodes in patients treated with OKT3. Renal function was equivalent in patients with rejection regardless of type of antirejection therapy used. Of patients treated for rejection, 22% had symptomatic CMV infections, which were divided equally between the two groups. Eighty-two patients received a single course of OKT3, 28 received two courses, and 2 patients received OKT3 three times. Only two patients developed antimurine antibodies that required abandoning OKT3 for the treatment of rejection. This study clearly demonstrates that the early use of OKT3 as primary treatment of rejection results in significant improvement of 2-year graft survival in recipients of first CAD kidney transplants. There is no increase in episodes in CMV in patients treated with OKT3 as primary therapy and no increase in patient mortality. Early use of OKT3 does not prevent or decrease incidence of subsequent rejection episodes. Renal function in surviving grafts is not improved in patients treated with OKT3 vs. PRED.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Treatment with anti-vascular cell adhesion molecule 1 monoclonal antibody induces long-term murine cardiac allograft acceptance.

Daily in vivo treatment of murine H-2d --> H-2b cardiac allograft recipients with 400 micrograms/day i.p. of M/K-2, a mAb to the endothelial adhesion molecule VCAM-1, resulted in prolongation of graft survival. The surviving allografts showed little of the histologic changes observed in acutely rejecting control allografts. When antibody treatment was discontinued after 20 days, grafts continued to function for at least 40 more days. This was approximately 30 days after mAb was no longer detectable by ELISA in the circulation, or by immunoperoxidase staining at the graft site. The most notable feature of grafts that survived 60 days was the presence of mild interstitial fibrosis. Endothelial reactivity was minimal with the mAbs MECA-32 and M/K-2, which have been used in previous studies to visualize the extensive endothelial inflammation that develops during untreated acute rejection. There was a mild cellular infiltrate containing T cells, but few macrophages. However, infiltrating T cells appeared to be inactive in that IL-2R+ cells were immunohistologically undetectable and mRNA for IL-2, IL-4, or IFN-gamma was undetectable by polymerase chain reaction. In general, the immunologic conditions in these long-term grafts differed from those seen in normal cardiac tissue, cardiac isografts, or cardiac allografts. These data demonstrate that M/K-2 mAb can suppress cardiac allograft rejection and induce long-term graft acceptance. This graft survival appears to be associated with the development of a unique state of immunity at the graft site.

Animals↗
PubMed1992

Importance of endothelial VCAM-1 for inflammatory leukocytic infiltration in vivo.

The microvascular endothelia of rejecting DBA/2----C57B1/6 murine cardiac allografts develop reactivity with the mAb M/K-2, which recognizes the murine homologue of the human leukocyte adhesion molecule VCAM-1. This reactivity does not develop in DBA/2----DBA/2 cardiac isografts or normal DBA/2 cardiac tissues. To determine whether endothelial VCAM-1 plays a role in allograft inflammation, cardiac allograft recipients were treated with M/K-2 antibody and monitored for leukocytic graft infiltration and graft survival. Treatment of the graft recipients with 200 micrograms/day M/K-2 Ig prolonged graft survival by 5 to 6 days (statistically significant); whereas treatment with 100 micrograms M/K-2 Ig every other day after transplant did not influence graft survival. Neither treatment interfered with leukocytic infiltration, as detected histologically or by limiting dilution analysis. The high dose treatment, but not the low dose treatment, resulted in high circulating levels of M/K-2, as detected by serum ELISA, and prominent antibody deposition on the graft vascular endothelia, as demonstrated by immunohistologic analysis. These data demonstrate that VCAM-1 is uniquely expressed on the vascular endothelia of rejecting murine cardiac allografts, and that a mAb to VCAM-1 can interfere with the allograft rejection process. Although this antibody can interfere with lymphocyte-endothelial adhesion in vitro, it has little effect on leukocytic infiltration in rejecting allografts suggesting that this process does not depend exclusively on VCAM-1 expression.

Animals↗
PubMed1992

Minimal model analysis of insulin sensitivity and glucose-mediated glucose disposal in type 1 (insulin-dependent) diabetic pancreas allograft recipients.

Decreased insulin sensitivity and glucose-dependent glucose disposal (glucose effectiveness) have been demonstrated in poorly-controlled Type 1 (insulin-dependent) diabetic patients. We have therefore examined the effects of successful pancreas transplantation that results in long-term physiologic normoglycaemia as measured by insulin sensitivity index and glucose effectiveness in 14 Type 1 diabetic recipients (Group 1) using the Bergman minimal model method. Their results were compared with those of five non-diabetic patients with kidney transplant alone (Group 2) and 10 healthy control subjects (Group 3). Mean plasma glucose levels were indistinguishable in Group 1 when compared to Groups 2 and 3. However, mean basal plasma insulin levels were two- and eight-fold greater in Group 1 (36 +/- 6 microU/ml) than in Group 2 (17 +/- 7 microU/ml) and Group 3 (4.5 +/- 0.6 microU/ml), respectively. Following intravenous glucose (t = 0 min) and tolbutamide (t = 20), peak incremental insulin levels were significantly (p less than 0.001) greater in Group 1 vs Groups 2 and 3. Mean insulin sensitivity index was 65% and 50% lower in Group 1 (2.89 +/- 0.45) and Group 2 (4.11 +/- 1.30), respectively, when compared to Group 3 (8.40 +/- 1.24 x 10(-1) min-1 (microU/ml)-1. In contrast, glucose effectiveness was similar in the three groups (Group 1, 2.48 +/- 0.26; Group 2, 2.05 +/- 0.21; and Group 3, 2.10 +/- 0.17 x 10(-2).min-1). We conclude that, despite prednisone-induced insulin resistance, normal glucose tolerance is achieved by hyperinsulinaemia and normalisation of glucose-dependent glucose disposal following pancreas-kidney transplantation in Type 1 diabetic patients.

Adult↗
PubMed1992

Sequential metabolic studies of pancreas allograft function in type 1 diabetic recipients.

We have previously shown that the loss of acute first phase insulin secretion precedes pancreas allograft rejection and development of glucose intolerance in Type 1 diabetic patients. In order to examine whether there is a progressive loss of phases of insulin secretion and beta-cell function in technically successful pancreas transplants during the first year, we measured glucose, insulin, and C-peptide responses to physiological (mixed meal) and pharmacological (IV glucose and IV glucagon) stimulation in 27 glucose-tolerant, insulin-independent allograft recipients at 3, 6, and 12 months. Mean +/- SE fasting serum glucose levels were normalized throughout the study period. Postprandial serum glucose profiles tended to increase by 12 months compared to 3 and 6 months, although peak glucose levels were not statistically different. Following pancreas transplantation, basal serum insulin levels were high at 3 months (163 +/- 17 pM), 6 months (165 +/- 22 pM), and 12 months (248 +/- 54 pM, p = NS) in the Type 1 diabetic pancreas allograft recipients when compared to normal (25 +/- 3 pM). We observed slight elevations in postprandial insulin and C-peptide profiles at 12 months compared to 3 and 6 months. Following IV glucose and glucagon stimulation, serum insulin and C-peptide levels as well as phases of insulin release did not differ over the 12-month study period. Similarly, the glucose decay constant (KG) was nearly identical at 3, 6, and 12 months. In summary, 1 year following successful whole cadaveric, heterotopic pancreas transplantation in Type 1 diabetic recipients, fasting serum glucose remains normalized, while postprandial glucose tends to rise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Combined kidney/pancreas transplantation at the Ohio State University Hospitals.

We conclude that combined kidney and pancreas transplantation is a safe and effective procedure to treat complicated Type I diabetic patients. It does carry significant potential for morbidity; therefore, it is essential that potential recipients understand these details prior to considering the procedure. Adequate preoperative screening for coronary artery disease is essential. The most difficult problem is dealing with early posttransplant dehydration and acidosis. More sensitive tools are needed to diagnose acute rejection in both combined kidney/pancreas recipients, as well as pancreas-alone grafts. Infectious complications are frequent, but most pose little morbidity. Currently, the incidence of early thrombosis is negligible. Even with these complications, overall excellent patient outcome demonstrates that kidney and pancreas transplantation should be the procedure of choice in well-selected Type 1 diabetics with end-stage renal disease.

Adult↗