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Biomedical subjects

M D Stegall

Publications and source records attributed to M D Stegall.

50 records · Page 3Linked to original sources
PubMed1990

Interstitial class II-positive cell depletion by donor pretreatment with gamma irradiation. Evidence of differential immunogenicity between vascularized cardiac allografts and islets.

We used an allograft pretreatment regimen involving lethal total-body gamma irradiation of donor rats eight days prior to transplantation to compare directly the immunogenicty of immediately-vascularized heart allografts with isolated, neovascularized pancreatic islet allografts. TBI pretreatment of heart donors (IHT) caused a modest prolongation in cardiac allograft survival compared with controls in a low-responding fully-allogeneic strain combination, Lewis-to-ACI. The addition of 10(5) donor-type dendritic cells (DCs) at the time of transplantation reversed the prolongation of IHT in this strain combination. Donor pretreatment with TBI did not lead to prolonged cardiac allograft survival in either a high-responding combination, ACI-to-Lewis, or in an MHC class II-compatible strain combination, F344-to-Lewis. In contrast, islets from irradiated donors (IIT) showed markedly prolonged survival in both low-responding (Lewis-to-ACI) and high-responding (W/F-to-Lewis) strain combinations. The addition of 10(5) donor-type DCs to the islets at the time of transplantation caused the rejection of only two of six IIT in the Lewis-to-ACI combination. Combined pretreatment regimens involving TBI-pretreated cardiac allografts--such as recipient immunosuppression with peritransplant cyclosporine (10 mg/kg on days 0, 1, and 2) or the combination of TBI (1000 cGy on day -3) and cyclophosphamide (300 mg/kg on day -5) in a pretreatment regimen--did not lead to synergistic graft prolongation in the low-responding Lewis-to-ACI combination. Immunohistologic studies showed that eight days after TBI rat hearts and islet were both greater than 90% depleted of class II (0X6+) interstitial dendritic cells while class I (0X18+) expression was unchanged. IIT are able to increase class II expression when donors are treated with recombinant gamma interferon (4000 U/day on days -3, -2, and -1). MLR data showed that ACI recipients of Lewis IIT reacted normally to donor (Lewis) and third-party (W/F) stimulator cells greater than 100 days after transplantation. The apparent greater immunogenicity of heart allografts as compared with islets in this model could be due to (1) a quantitative difference between the number of residual class II-positive cells in hearts and islets or a greater nnon-MHC antigenic load in the heart grafts given its larger size, or (2) a quanlitative difference between hearts and islets due to the presence of a vascular endothelium in the immediately vascularized heart that can present alloantigen and provide a major stimulus to rejection.

Animals↗
PubMed1990

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function.

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.

Antibodies, Anti-Idiotypic↗
PubMed1990

UVB pretreatment of rat bone marrow allografts. Prevention of GVHD and induction of allochimerism and donor-specific unresponsiveness.

Ultraviolet B irradiation has been used to pretreat blood and islets to prevent subsequent graft rejection. In this study the optimal dose of UVB irradiation of bone marrow was determined in syngeneic recipients and was subsequently applied to in-vitro treatment of bone marrow allografts. UVB pretreatment of donor bone marrow inoculum led to complete prevention of GVHD in allogeneic rat recipients without major marrow or other toxicity. Long-standing recipients of allogeneic UVB-BM became stable adult chimeras. The recipients of allogeneic BM were populated by donor-type peripheral blood lymphocytes and did not reject host or donor-type heart grafts. The BM allograft recipients were immunocompetent as measured by their ability to normally reject third-party cardiac allografts. We suggest that the prevention of GVHD and induction of stable chimerism in adult recipients of allogeneic UVB-BM may be mediated by suppressor mechanisms.

Animals↗
PubMed1989

Pancreatic islet transplantation in cynomolgus monkeys. Initial studies and evidence that cyclosporine impairs glucose tolerance in normal monkeys.

Using a model of streptozotocin-induced, ketosis-prone, insulin-dependent diabetes mellitus (IDDM) in the cynomolgus monkey, we performed 11 intraportal transplants of collagenase-digested, Ficoll-purified pancreatic islets (9 ABO-compatible allografts and 2 concordant baboon xenografts). Islets were pretreated with ultraviolet-B irradiation and recipients received cyclosporine A immunosuppression. Two grafts never functioned, five grafts showed evidence of partial function, and four grafts (three allografts and one xenograft) showed evidence of good function, with the animals independent of exogenous insulin with morning fasting blood glucose levels less than 200 mg/dl. Because two grafts functioned only after CsA was either tapered or discontinued, we performed a related study that showed that therapeutic doses of CsA (morning trough serum level 150-250 ng/ml) impaired intravenous glucose tolerance tests (IVGTT) of normal monkeys and may contributed to graft dysfunction in our islet transplantation model. The results show that there is a decrease in release of serum insulin during an IVGTT leading to impairment of glucose utilization, while serum glucagon remains unaffected. After cessation of CsA, the IVGTT did not return to normal for 28 days. Oral glucose tolerance tests were unaffected in CsA-treated monkeys. These initial studies show that the streptozotocin-diabetic monkey is a valuable model to study IDDM and islet transplantation in nonhuman primates. We also confirm studies in rodents, dogs, and sheep by showing that CsA partially inhibits beta cell function in normal monkeys.

Animals↗
PubMed1989

Humoral immunity in allograft rejection. The role of cytotoxic alloantibody in hyperacute rejection and enhancement of rat cardiac allografts.

The role of humoral immunity in graft rejection in the rat model remains controversial. Passive transfer of cytotoxic alloantibody (CAA) has resulted either in hyperacute rejection or in graft enhancement. This study examines the effect of transfer of CAA on cardiac allograft survival in three rat strain combinations that are fully mismatched at the major histocompatibility (MHC) loci. Strain-specific immune responsiveness in donor-recipient pairs varied from low (Lewis-to-ACI) to high (ACI-to-Lewis) as measured by mixed lymphocyte reactions. CAA was obtained from rats sensitized by three successive skin grafts at weekly intervals. Group 1 (high responder recipients), which consisted of Lewis rats presensitized to ACI and had a lymphocytotoxicity titer of 1:512 to 1:2048, rejected ACI cardiac allografts in 10.8 +/- 7.2 hr compared with 6.5 +/- 0.5 days in naive controls (p less than 0.001). Injection of 1 ml of high-titer CAA into naive Lewis rats immediately after ACI cardiac grafting led to hyperacute rejection of ACI hears in 2.1 +/- 0.8 hr while 1 ml of CAA followed by 2 ml of guinea pig complement (GPC) resulted in even faster rejection (mean survival time (MST) of 23.8 +/- 4.7 min). Injection of 2 ml GPC alone or in combination with 1 ml naive Lewis serum had no effect on graft survival. Multiple pretransplant injections of 1 ml of CAA on days -3, -2,-1, and 0 relative to transplantation resulted in significant prolongation of allograft survival (MST of 10.3 +/- 0.3 days; P less than 0.01). In group 2 (intermediate responder recipients), where Lewis rats were presensitized to WF strain and where cytotoxicity titer was 1:16 to 1:256, the recipients rejected WF hearts in 23.8 +/- 5.8 hr compared with 6.8 +/- 0.8 days in unsensitized control recipients (P less than 0.001). Injection of 1 ml of Lewis anti-WF CAA resulted in prolonged graft survival of 9.7 +/- 3.5 days, while injection of 1 ml of CAA followed by 2 ml of GPC caused hyperacute rejection in 104 +/- 61.7 min. Pretransplant injections of CAA on days -3, -2, -1, and 0 resulted in enhancement, with an MST of 16.3 +/- 1.3 days (P less than 0.001). In group 3 (low responder recipients), ACI presensitized to Lewis developed a cytotoxicity titer of 1:2 to 1:32 and rejected Lewis hearts in 5.3 +/- 0.4 days compared with 10.6 +/- 1.0 days in naive recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Preliminary experience with a cuffed ePTFE graft for hemodialysis vascular access.

The purpose of this study was to determine graft patency and blood flow rates in recipients of a new cuffed ePTFE graft (Venaflo graft) used for hemodialysis access. A pilot study was conducted with 12 (7 men, 5 women) consecutive patients (age range, 36-76 yr; mean, 65 yr). All patients were recipients of a new cuffed PTFE graft placed for hemodialysis access. Seven were high risk because of a prior history of clotted hemodialysis accesses (1-6; mean, 3.3). Blood flow rates were determined by ultrasound dilution technique at 3 month intervals. One year and 2 year overall graft patency rates were 90.9% and 68.2%, respectively. One graft (high risk, six prior grafts) was lost to thrombosis in the first year; two grafts (one high risk, four prior grafts) were lost to thrombosis in the second year of follow-up. No graft thrombosis resulted from stenosis at the graft-vein anastomosis. Blood flow rates ranged from 550 to 2,110 ml/min (mean, 1,086 ml/min; n = 8) when first measured 3 months after graft placement. Similar flow rates were observed at 12 months (mean, 1,043 ml/min; n = 7) and 24 months (mean, 1,014 ml/min; n = 4) in grafts available for comparison. Dialysis flow rates in excess of 350 ml/min were possible with all patent grafts. A cuffed ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis.

Adult↗