Minimally invasive surgery for thoracoabdominal aortic aneurysms.

Open surgical repair of thoracoabdominal aortic aneurysms (TAAA) remains a highly morbid procedure. In recent years, several minimally invasive techniques have been introduced to treat TAAA. These include hybrid procedures and purely endovascular approaches using modified aortic endografts. Although still investigational, this burgeoning technology has the potential to improve outcomes in TAAA repair, as well as to circumvent the morbidity and mortality associated with the traditional surgical approach to TAAA. While the reported experience is limited to several institutional case series, results are encouraging, and suggest that fenestrated and branched endografts are likely to figure prominently in the management of TAAA in the future. An overview of these minimally invasive techniques, as well as the role of computer-assisted imaging analysis, is provided.

Double-barrel technique for preservation of aortic arch branches during thoracic endovascular aortic repair.

Thoracic endovascular aortic repair (TEVAR) may involve either planned or inadvertent coverage of aortic branch vessels when stent grafts are implanted into the aortic arch. Vital branch vessels may be preserved by surgical debranching techniques or by placement of additional stents to maintain vessel patency. We report our experience with a double-barrel stent technique used to maintain aortic arch branch vessel patency during TEVAR. Seven patients underwent TEVAR using the double-barrel technique, with placement of branch stents into the innominate (n = 3), left common carotid (n = 3), and left subclavian (n = 1) arteries alongside an aortic stent graft. Gore TAG endografts were used in all cases, and either self-expanding stents (n = 6) or balloon-expandable (n = 1) stents were utilized to maintain patency of the arch branch vessels. In three cases the double-barrel stent technique was used to restore patency of an inadvertently covered left common carotid artery. Four planned cases involved endograft deployment proximally into the ascending aorta with placement of an innominate artery stent (n = 3) and coverage of the left subclavian artery with placement of a subclavian artery stent (n = 1). TEVAR using a double-barrel stent was technically successful with maintenance of branch vessel patency and absence of type I endoleak in all seven cases. One case of zone 0 endograft placement with an innominate stent was complicated by a left hemispheric stroke that was attributed to a technical problem with the carotid-carotid bypass. On follow-up of 2-18 months, all double-barrel branch stents and aortic endografts remained patent without endoleak, migration, or loss of device integrity. The double-barrel stent technique maintains aortic branch patency and provides additional stent-graft fixation length during TEVAR to treat aneurysms involving the aortic arch. Moreover, the technique uses commercially available devices and permits complete aortic arch coverage (zone 0) without a sternotomy. Although initial outcomes are encouraging, long-term durability remains unknown.

Endovascular stent graft repair of a thoracic aortic gunshot injury.

Endovascular treatment approaches offer minimally invasive alternative strategies for the management of vascular injuries. While endovascular stent graft repair of blunt injury to the thoracic aorta is well described, there are few reports of its application for treatment of penetrating injuries of the thoracic aorta. We report the successful treatment of a through-and-through gunshot injury of the thoracic aorta and review how this technology may be applied for the treatment of penetrating thoracic aortic injury.

Inclusion of the E3 region in an adenoviral vector decreases inflammation and neointima formation after arterial gene transfer.

Adenoviral vectors are promising agents for vascular gene transfer. Their use, however, is limited by inflammatory host responses, neointima formation, and brevity of transgene expression. Inclusion of the immunomodulatory adenoviral E3 genes in a vector might prevent inflammation and neointima formation and prolong transgene expression. We compared 2 adenoviral vectors in a model of in vivo gene transfer to rabbit arteries. Both vectors expressed a luciferase reporter gene. One vector (AdE3Luc) contained the adenovirus early 3 (E3) region and the other (AdRSVLuc) lacked E3. Expression of E3 genes by AdE3Luc was confirmed in vitro and in vivo. Arteries transduced with AdE3Luc had substantially and significantly less inflammation (fewer T cells and lower levels of vascular cell adhesion molecule-1 and intercellular adhesion molecule 1 expression) and decreased neointima formation 14 days after gene transfer. Luciferase expression from the 2 vectors was equivalent, however, at both 3 and 14 days after gene transfer. Expression of E3 had no systemic immunosuppressive effects, as measured by peripheral blood counts and by assays for serum antibodies to adenovirus. We conclude that expression of E3 significantly decreases adenovirus-induced arterial wall inflammation and neointima formation. Because inflammation and neointima formation are major barriers to the clinical application of adenoviral vectors, use of E3-containing vectors improves the promise of adenovirus-mediated arterial gene transfer.

Extended iliac exposure from the groin.

Knowledge of iliac artery and inguinal anatomy enables extraperitoneal exposure of the iliac arteries for surgical treatment of unilateral inflow disease. A method is presented for exposing the distal common iliac artery, the iliac bifurcation, and the full length of the external iliac artery by detachment and retraction of the inguinal ligament though a single extended groin incision. The indications for unilateral iliac artery exposure, revascularization, surgical anatomy, and technique of iliofemoral exposure through a single, extended groin incision are presented. Extended iliac exposure through a single, extraperitoneal exposure facilitates all methods of unilateral iliac revascularization and provides access for delivery of endovascular devices.

The clinical relevance of microbiologic testing: a comparative analysis of microbiologic samples secured from the same sites and cultured in two independent laboratories.

A field study using five different private periodontal practices was conducted; it compared two microbiologic culture samples simultaneously secured from the same sites within 23 individual patients and submitted for bacterial identification and antibiotic sensitivity testing to two separate laboratories. The results from the two laboratories were often different. In no instance did both laboratories agree on the presence of identical bacterial species. When only bacteria above threshold levels were compared, agreement was found in only nine of 23 cases. When examining antibiotic sensitivity, using 100% kill of all tested pathogens as the ideal, agreement between the two laboratories was poor. The laboratories agreed on the use of amoxicillin 17% of the time, tetracycline 26% of the time, and metronidazole 48% of the time. The use of amoxicillin and metronidazole in combination yielded a 78% agreement when the results of both laboratories were combined. It would appear from the data that the empirical use of amoxicillin-metronidazole combination therapy may be more clinically sound and cost effective than culturing and antibiotic selection based on the results of culture from any single microbiologic testing laboratory.

Germline incorporation of a replication-defective adenoviral vector in mice does not alter immune responses to adenoviral vectors.

The utility of adenoviral vectors is limited by immune responses to adenoviral antigens. We sought to develop immune-competent mice in which the immune response to adenoviral antigens was selectively absent. To do so, we generated mice that were transgenic for a replication-defective vector. Adenoviral antigens might be seen as self-antigens by these mice, and the mice could exhibit immunologic tolerance after postnatal exposure to adenoviral vectors. In addition, characterization of these mice could reveal potential consequences of germline transmission of an adenoviral vector, as might occur in a gene therapy trial. Injection of a "null" (not containing a transgene) E1, E3-deleted vector genome into mouse zygotes yielded five founders that were capable of transmitting the vector genome. Among offspring of these mice, transgenic pups were significantly underrepresented: 108 of 255 pups (42%) were transgenic (P<0.02 versus expected frequency of 50%). Postnatal transgenic mice, however, had no apparent abnormalities. Persistence of an adenoviral vector after intravenous injection was equivalent in livers of transgenic mice and their nontransgenic littermates. Transgenic and nontransgenic mice also had equivalent humoral and cellular immune responses to adenoviral vector injection. Mice that are transgenic for an E1, E3-deleted adenoviral genome can be easily generated; however, they are not tolerant of adenovirus. Moreover, germline transmission of an adenoviral vector genome does not prevent generation of a robust immune response after exposure to adenoviral antigens.

Positron emission tomography with f18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma.

OBJECTIVES: The purpose of this study was to evaluate the utility of positron emission tomography with F18-fluorodeoxyglucose in the preoperative evaluation and staging of malignant mesothelioma in patients who were candidates for aggressive combined modality therapy. METHODS: Eighteen consecutive patients with biopsy-proven malignant mesothelioma underwent positron emission tomographic scanning. The results of positron emission tomographic imaging were compared with results obtained by computed tomography, mediastinoscopy, thoracoscopy, and pathologic examination of surgical specimens. All patients fasted and received an average of 14.5 +/- 2.7 mCi of F18-fluorodeoxyglucose for positron emission tomographic scanning. Attenuation-corrected whole-body and regional emission images of the chest and upper abdomen were acquired and formatted into transaxial, coronal, and sagittal images. RESULTS: All primary malignant mesotheliomas accumulated F18-fluorodeoxyglucose, and the mean standardized uptake value was 7. 6 (range, 3.33-14.85; n = 9). There were no false-negative results of positron emission tomography. Identification of occult extrathoracic metastases by positron emission tomography was the basis for excluding two patients from surgical therapy. There were two false-positive results of positron emission tomography: increased F18-fluorodeoxyglucose uptake in the contralateral chest that was negative by thoracoscopic biopsy (n = 1) and increased abdominal F18-fluorodeoxyglucose uptake after partial colectomy for diverticular disease (n = 1). CONCLUSIONS: Positron emission tomography can identify malignant pleural mesothelioma and appears to be a useful noninvasive staging modality for patients being considered for aggressive combined modality therapy.

A non-cleavable mutant of Fas ligand does not prevent neutrophilic destruction of islet transplants.

BACKGROUND: Fas ligand (FasL) mediates apoptosis of susceptible Fas-expressing lymphocytes, and may contribute to the maintenance of peripheral tolerance. In transplantation models, however, artificial expression of FasL on cellular as well as islet transplants results in accelerated rejection by neutrophils. The mechanism of the neutrophilic response to FasL expression is unknown. FasL, like other members of the tumor necrosis factor family, is cleaved to a soluble form by metalloproteases. We tested the hypothesis that soluble FasL (sFasL) was responsible for neutrophil migration by creating a non-cleavable mutant of FasL. METHODS: Three mutants of FasL with serial deletions in the putative proteolytic cleavage site of human FasL were made using inverse polymerase chain reaction. The relative fractions of sFasL and membrane-bound FasL were assessed by Western blot and immunoprecipitation, as well as by cytotoxicity assay using Fas-expressing target cells. The fully non-cleavable mutant was transduced into murine islets as well as myoblasts and tumor cell lines, and tested in a murine transplantation model. RESULTS: Serial deletions in the putative metalloprotease site of FasL resulted in a fully non-cleavable mutant of FasL (ncFasL). Expression of ncFasL in tumor lines induced higher levels of apoptosis in Fas bearing targets than wild-type FasL. Transplantation of ncFasL-expressing islets under the kidney capsule of allogenic mice resulted in accelerated rejection identical to that seen with wild-type Fas ligand-expressing islets. Myoblasts and tumor cell lines expressing ncFasL also induced neutrophil infiltration. CONCLUSIONS: Membrane-bound Fas ligand is fully capable of inducing a neutrophilic response to transplants, suggesting an activation by Fas ligand of neutrophil chemotactic factors.

Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall.

The utility of adenoviral vectors for arterial gene transfer is limited by the brevity of their expression and by inflammatory host responses. As a step toward circumventing these difficulties, we used a rabbit model of in vivo arterial gene transfer to test 3 second-generation vectors: a vector containing a temperature-sensitive mutation in the E2A region, a vector deleted of E2A, and a vector that expresses the immunomodulatory 19-kDa glycoprotein (gp19k) from adenovirus 2. Compared with similar first-generation vectors, the second-generation vectors did not significantly prolong beta-galactosidase transgene expression or decrease inflammation in the artery wall. Although cyclophosphamide ablated the immune and inflammatory responses to adenovirus infusion, it only marginally prolonged transgene expression (94% drop in expression between 3 and 14 days). In experiments performed with "null" adenoviral vectors (no transgene), loss of vector DNA from the arterial wall was also rapid (>99% decrease between 1 hour and 14 days), unrelated to dose, and only marginally blunted by cyclophosphamide. Thus, the early loss of transgene expression after adenoviral arterial gene transfer is due primarily to loss of vector DNA, is not correlated with the presence of local vascular inflammation, and cannot be prevented by use of E2A-defective viruses, expression of gp19k, or cyclophosphamide-mediated immunosuppression. Adenovirus-induced vascular inflammation can be prevented by cyclophosphamide treatment or by lowering the dose of infused virus. However, stabilization of adenovirus-mediated transgene expression in the arterial wall is a more elusive goal and will require novel approaches that prevent the early loss of vector DNA.

Expression of Fas ligand in arteries of hypercholesterolemic rabbits accelerates atherosclerotic lesion formation.

Fas ligand (FasL) is expressed by cells of the arterial wall and is present in human atherosclerotic lesions. However, the role of FasL in modifying the initiation and progression of atherosclerosis is unclear. To investigate the role of arterial FasL expression in the development of atherosclerosis, we first established a model of primary lesion formation in rabbit carotid arteries. In this model, infusion of adenoviral vectors into surgically isolated, nondenuded arteries of hypercholesterolemic rabbits leads to the formation of human-like early atherosclerotic lesions. Expression of FasL in arterial endothelium in this model decreased T-cell infiltration and expression of vascular cell adhesion molecule-1 but did not affect expression of intercellular adhesion molecule-1. Intimal lesions grew more rapidly in FasL-transduced arteries than in arteries transduced with a control adenovirus that did not express a transgene. Total intimal macrophage accumulation was increased in FasL-transduced arteries; however, the proportion of lesion area occupied by macrophages was not elevated. The accelerated lesion growth was primarily due to the accumulation of intimal smooth muscle cells with a synthetic proliferative phenotype. There was no significant apoptosis in FasL-transduced or control arteries and no granulocytic infiltrates. Thus, the net result of elevated FasL expression is to accelerate atherosclerotic lesion growth by increasing lesion cellularity. Vascular expression of FasL may contribute to the progression of atherosclerosis.

Isolated inferior mesenteric artery revascularization for chronic visceral ischemia.

PURPOSE: Complete visceral artery revascularization is recommended for the treatment of chronic visceral ischemia. However, in rare cases, it may not be possible to revascularize either the celiac or superior mesenteric (SMA) arteries. We have managed a series of patients with isolated revascularization of the inferior mesenteric artery (IMA) and now report our experience gained over a period of three decades. METHODS: Records were reviewed from 11 patients with chronic visceral ischemia who underwent isolated IMA revascularization (n = 8) or who, because of failure of concomitant celiac or SMA repairs, were functionally left with an isolated IMA revascularization (n = 3). All the patients had symptomatic chronic visceral ischemia documented with arteriography. Five patients had recurrent visceral ischemia after failed visceral revascularization, and two patients had undergone resection of ischemic bowel. The celiac or the SMA was unsuitable for revascularization in five cases, and extensive adhesions precluded safe exposure of the celiac or the SMA in five cases. IMA revascularization techniques included: bypass grafting (n = 4), transaortic endarterectomy (n = 4), reimplantation (n = 2), and patch angioplasty (n = 1). RESULTS: There was one perioperative death, and the remaining 10 patients had cured or improved conditions at discharge. One IMA repair thrombosed acutely but was successfully revascularized at reoperation. The median follow-up period was 6 years (range, 1 month to 13 years). Two patients had recurrent symptoms develop despite patent IMA repairs and required subsequent visceral revascularization; interruption of collateral circulation by prior bowel resection may have contributed to recurrence in both patients. Objective follow-up examination with arteriography or duplex scanning was available for eight patients at least 1 year after IMA revascularization, and all underwent patent IMA repairs. There were no late deaths as a result of bowel infarction. CONCLUSION: Isolated IMA revascularization may be useful when revascularization of other major visceral arteries cannot be performed and a well-developed, intact IMA collateral circulation is present. In this select subset of patients with chronic visceral ischemia, isolated IMA revascularization can achieve relief of symptoms and may be a lifesaving procedure.

Adventitial delivery minimizes the proinflammatory effects of adenoviral vectors.

PURPOSE: Adenovirus-mediated arterial gene transfer is a promising tool in the study of vascular biology and the development of vascular gene therapy. However, intraluminal delivery of adenoviral vectors causes vascular inflammation and neointimal formation. Whether these complications could be avoided and gene transfer efficiency maintained by means of delivering adenoviral vectors via the adventitia was studied. METHODS: Replication-defective adenoviral vectors encoding a beta-galactosidase (beta-gal) gene (AdRSVnLacZ) or without a recombinant gene (AdNull) were infused into the lumen or the adventitia of rabbit carotid arteries. Two days after infusion of either AdRSVnLacZ (n = 8 adventitial, n = 8 luminal) or AdNull (n = 4 luminal), recombinant gene expression was quantitated by histochemistry (performed on tissue sections) and with a beta-gal activity assay (performed on vessel extracts). Inflammation caused by adenovirus infusion was assessed 14 days after infusion of either AdNull (n = 6) or vehicle (n = 6) into the carotid adventitia. Inflammation was assessed by means of examination of histologic sections for the presence of neointimal formation and infiltrating T cells and for the expression of markers of vascular cell activation (ICAM-1 and VCAM-1). To measure the systemic immune response to adventitial infusion of adenovirus, plasma samples (n = 3) were drawn 14 days after infusion of AdNull and assayed for neutralizing antibodies. RESULTS: Two days after luminal infusion of AdRSVnLacZ, approximately 30% of luminal endothelial cells expressed beta-gal. Similarly, 2 days after infusion of AdRSVnLacZ to the adventitia, approximately 30% of adventitial cells expressed beta-gal. beta-gal expression was present in the carotid adventitia, the internal jugular vein adventitia, and the vagus nerve perineurium. Elevated beta-gal activity (50- to 80-fold more than background; P <.05) was detected in extracts made from all AdRSVnLacZ-transduced arteries. The amount of recombinant protein expression per vessel did not differ significantly between vessels transduced via the adventitia (17.1 mU/mg total protein [range, 8.1 to 71.5]) and those transduced via a luminal approach (10.0 mU/mg total protein [range, 3.9 to 42.6]). Notably, adventitial delivery of AdNull did not cause neointimal formation. In addition, vascular inflammation in arteries transduced via the adventitia (ie, T-cell infiltrates and ICAM-1 expression) was confined to the adventitia, sparing both the intima and media. Antiadenoviral neutralizing antibodies were present in all rabbits after adventitial delivery of AdNull. CONCLUSION: Infusion of adenoviral vectors into the carotid artery adventitia achieves recombinant gene expression at a level equivalent to that achieved by means of intraluminal vector infusion. Because adventitial gene transfer can be performed by means of direct application during open surgical procedures, this technically simple procedure may be more clinically applicable than intraluminal delivery. Moreover, despite the generation of a systemic immune response, adventitial infusion had no detectable pathologic effects on the vascular intima or media. For these reasons, adventitial gene delivery may be a particularly useful experimental and clinical tool.

Adenoviral gene transfer in arteries of hypercholesterolemic nonhuman primates.

Arterial gene transfer with adenoviral vectors is a promising approach for the treatment and prevention of vascular disorders. However, in small animals such as rats and rabbits adenoviral vectors can have deleterious effects on the artery wall. The effects of adenovirus in primate arteries have not been studied. AdRSVn-LacZ, a replication-defective adenoviral vector, was delivered to the left brachial arteries of six hypercholesterolemic cynomolgus monkeys; right brachial arteries received vehicle only. Serum was collected before gene transfer and at vessel harvest 9 or 10 days later. Recombinant gene expression was present in occasional endothelial cells of transduced arteries, and all animals generated neutralizing antibodies. In transduced arteries, immunostaining revealed a fourfold increase in intimal and medial macrophage accumulation (p < 0.05); intimal cellularity was also significantly increased (twofold; p < 0.05). T cell density and total cellular proliferation (determined by bromodeoxyuridine labeling) were unaffected. In hypercholesterolemic nonhuman primates, adenoviral vectors increase vessel wall inflammation and promote the progression of early atherosclerotic lesions. The long-term consequences of these observations remain unclear; however, a better understanding of host responses to specific vector systems appears necessary for the development of safe and effective approaches to human vascular gene therapy.

Reoperation for recurrent chronic visceral ischemia.

PURPOSE: Recurrent visceral ischemia after a failed visceral revascularization occurs in up to one third of patients, yet no comprehensive report has described the management of this problem. The purpose of this study was to examine the presentation, surgical management, and outcome of patients with recurrent visceral ischemia. METHODS: Between 1959 and 1997, 109 patients underwent primary visceral revascularization at the University of California, San Francisco. Nineteen patients (17.4%) had recurrent visceral ischemia (12 chronic visceral ischemia, seven acute visceral ischemia). Fourteen additional patients with recurrent chronic visceral ischemia were referred after failed primary revascularization (two patients underwent multiple operations before referral). Thirty visceral reoperations were performed for recurrent visceral ischemia in 24 patients (10 patients with recurrence at University of California, San Francisco, 14 referred patients). Symptom-free and overall survival rates were determined by life table analysis. RESULTS: Of seven patients (6.4%) who had recurrent acute visceral ischemia, six (85.7%) died of bowel infarction. Twelve patients (11%) had recurrent chronic visceral ischemia. Patients with recurrent chronic visceral ischemia received their diagnoses earlier and lost less weight than at their initial presentation (p = 0.004 and 0.001, respectively). Recurrent ischemia was associated with younger age, greater weight loss, and modification of surgical technique at the time of initial operation (p = 0.5, 0.009, and 0.02, respectively). For 20 (90.9%) of the 22 first reoperations, antegrade aortovisceral bypass (n = 10) or transaortic visceral endarterectomy (n = 10) was used. Multiple techniques (four antegrade bypass, two retrograde bypass, one endarterectomy, one anastomotic revision) were used in the eight second or third reoperations. Postoperative mortality and complication rates were 6.7% and 33.3%, respectively. Symptoms recurred in six of 22 patients (27.3%) after the first reoperation, three of whom were cured or improved after additional reoperations. The life table symptom-free survival rate after reoperation was 77.3% and 62.8% at 1 and 5 years, respectively. The life table overall survival rate after reoperation was 74.6% at 5 years. CONCLUSIONS: Recurrent visceral ischemia is not uncommon after primary visceral revascularization. These results show that reoperation for recurrent chronic visceral ischemia can be accomplished safely and effectively with established revascularization techniques. Furthermore, after repeat visceral revascularization patients achieve durable relief of symptoms and have life expectancy rates comparable with those of patients who undergo primary visceral revascularization.

Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock.

The role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) was studied in preterm and term neonates with sepsis and shock. CGRP levels in blood were measured by RIA. The identity of immunoreactive CGRP (irCGRP) in adult and infant human blood was confirmed by reverse phase-HPLC. CGRP levels were analyzed in a total of 189 samples (95 from cord blood and 94 from neonates). The gestational ages ranged from 24 to 43 wk, and the birth weights ranged from 520 to 4445 g. Cord samples were collected immediately after delivery and infant blood samples were collected within 12 h of birth. Samples were coded, and the data were assigned to groups after determination of CGRP levels. There was a weight- and gestation-dependent increase in irCGRP in the newborn population. The direct correlation of circulating CGRP with ascending birth weight and gestation may have significance in the development of the fetus. Infants with and without certain complications were grouped in 500-g intervals. CGRP levels in cord blood were significantly elevated when certain stressful situations existed in the mother. These included culture-positive chorioamnionitis, placental abruption, and severe preeclampsia. There was a similar elevation in CGRP in patient blood in infants with culture-positive sepsis and/or shock with blood pressure <2 SD from the mean for corresponding gestation. CGRP levels did not differ between male and female infants and did not appear to be influenced by type of delivery (vaginal versus cesarean section). There was no significant difference in CGRP level between cord and patient blood in preterm neonates, but at term gestation cord blood levels were slightly higher than those in the patient blood. These results suggest that inflammation and hemodynamic imbalance (e.g. shock) are associated with increased in CGRP levels in the circulation in neonates. Future studies will focus on the biologic effects of elevated CGRP during neonatal complications and will examine the utility of CGRP measurement for diagnosis and treatment of disease in preterm infants.

Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction.

Fas ligand is believed to mediate immune privilege in a variety of tissues, including the eye, testis, and a subset of tumors. We tested whether expression of Fas ligand on pancreatic islets either following adenoviral or germline gene transfer could confer immune privilege after transplantation. Islets were infected with an adenoviral vector containing the murine Fas ligand cDNA (AdFasL), and were transplanted into allogenic diabetic hosts. Paradoxically, AdFasL-infected islets underwent accelerated neutrophilic rejection. The rejection was T cell and B cell independent and required Fas protein expression by host cells, but not on islets. Similarly, transgenic mice expressing Fas ligand in pancreatic beta cells developed massive neutrophilic infiltrates and diabetes at a young age. Thus, Fas ligand expression on pancreatic islets results in neutrophilic infiltration and islet destruction. These results have important implications for the development of Fas ligand-based immunotherapies.