Successful resection of a primary angiosarcoma of the azygos vein: A case report.

A 63-year-old woman was admitted to our department for the investigation of superior vena cava (SVC) syndrome. Computed tomography revealed an azygos tumor extending into the SVC. Video-assisted thoracic surgery (VATS) was performed to remove the distal end of the azygos vein in the left lateral position, followed by complete resection of the entire tumor under median sternotomy in the supine position. The histological diagnosis was a primary angiosarcoma of the azygos vein. The patient was discharged without any complications and is now alive and tumor-free 24 months after surgery. In addition, contrast-enhanced computed tomography revealed no graft occlusion in the two reconstructed brachiocephalic veins. Thoracoscopic surgery in the lateral position is useful for safe and reliable complete resection of a tumor arising from the azygos vein.

Graft Protective and Intercellular Immunomodulatory Effects by Adoptive Transfer of an Agonistic Anti-BTLA mAb (3C10) Induced CD4+CD25+ Regulatory T Cells in Murine Cardiac Allograft Transplant Model.

BACKGROUND: We demonstrated that an agonistic anti-B and T lymphocyte attenuator antibody (3C10) prolonged cardiac survival by inducing regulatory T cells (Treg). However, the mechanisms of immune tolerance in the recipients remained unclear. In this study, we investigated the graft-protective and intercellular immunomodulatory effects of adoptive transfer (AT) of 3C10-induced Tregs in a murine cardiac allograft transplant model. METHODS: Thirty days after transplantation of a C57BL/6 heart into the primary 3C10-treated CBA recipients, splenic CD4+CD25+ cells from these recipients (3C10/AT group) or naïve CBA mice (no-treatment group) were adoptively transferred into secondary CBA recipients with a C57BL/6 heart. To confirm the requirement for 3C10-induced Tregs, we administered an anti-interleukin-2 receptor alpha antibody (PC-61) to secondary CBA recipients. Additionally, histologic and fluorescent staining, cell proliferation analysis, flow cytometry, and donor-specific antibody (DSA) measurements were performed. RESULTS: 3C10/AT-treated CBA recipients resulted in significantly prolonged allograft survival (median survival time [MST], >50 days). Allografts displayed prolonged function with preservation of vessel structure by maintaining high numbers of splenic CD4+CD25+Foxp3+ Treg and intramyocardial CD4+Foxp3+ cells. DSA levels were suppressed in 3C10/AT-treated CBA recipients. Moreover, PC-61 administration resulted in a shorter MSTs of cardiac allograft survivals, a detrimental increase in DSA production, and enhanced expression of programmed cell death (PD)-1. CONCLUSION: AT of 3C10-induced Tregs may be a promising graft-protective strategy to prolong allograft survival and suppress DSA production, driven by the promotion of splenic and graft-infiltrating Tregs and collaboration with PD-1+ T cells and Treg.

Placement of stent grafts with different calibers into the true and false lumens of anastomotic aneurysms after descending aortic replacement for aortic dissection.

Anastomotic aneurysms present as a life-threatening emergency after descending aortic replacement for aortic dissection. Thoracic endovascular aneurysm repair (TEVAR) has been performed since the early 2000s for complicated cases in which re-thoracotomy cannot be adopted. We report the case of a 57-year-old male patient, during a 5-year follow-up after descending aortic replacement for aortic dissection, developed aneurysm expansion around the false lumen on the peripheral side of the artificial graft. Considering the risk and the patient's desires, we opted to perform TEVAR with different calibers into the true and false lumens "modified kissing stents technique". His postoperative course was uneventful without any complications. This case highlights the utility of the modified kissing stents technique for anastomotic aneurysms after descending aortic replacement for aortic dissection using stent grafts with different calibers into the true and false lumens.

Novel and Efficient Method for Diagnosing Infective Endocarditis Using 16S Ribosomal RNA Gene Amplicon Sequence.

We present 2 cases that both developed infective endocarditis and underwent mitral valve replacement. In addition to positive blood culture and echocardiographic findings, such as vegetation or mitral valve perforation, the 16S ribosomal RNA gene amplicon sequence approach used was helpful for disease diagnosis. (Level of Difficulty: Intermediate.).

A successful case of patch angioplasty with bovine pericardium XenoSure® to the common femoral artery after endarterectomy.

INTRODUCTION AND IMPORTANCE: The number of patients with chronic limb-threatening ischemia has increased in recent years. Herein, we report a rare case of angioplasty with a bovine pericardial patch in a patient with severe stenosis of the common femoral artery. CASE PRESENTATION: We report a case of a 73-year-old female with intermittent claudication. Ankle-brachial index (ABI) measurements showed a significant decrease of 0.52 on the left, and angiography revealed total occlusion on the left common femoral artery (CFA). Considering additional skin incisions, postoperative wound infection, and potential graft sampling, endarterectomy of the left CFA and patch angioplasty with the bovine pericardium (XenoSure®) were performed. The operative computed tomography showed no stenosis and the ABI improved from 0.52 to 1.15. Additionally, no stenosis, calcification, or dilatation was observed during the follow-up one year after the operation. CLINICAL DISCUSSION: Various types of peripheral arterial repair were performed after endarterectomy. Autologous vein grafts and vascular prostheses are frequently used considering the background of each patient. Using bovine pericardium over other devices has several advantages, including no additional skin incisions to obtain the patches, resistance to infection, no oozing from the device itself, less bleeding from the suture site, and ease of hemostasis after the puncture under additional endovascular treatment. This case may be a good implication when deciding which device to use in complicated patients. CONCLUSION: This case provides valuable insight into successful patch angioplasty after endarterectomy without any complications, highlighting the utility of XenoSure® in the treatment of this disease.

Surgical treatment of papillary fibroelastoma of the pulmonary valve: a case report.

BACKGROUND: Cardiac papillary fibroelastoma (PFE) is a rare tumor, and especially rare when found on the pulmonary valve. CASE PRESENTATION: We report the case of a 70-year-old woman patient with a pulmonary valve PFE diagnosed incidentally during a follow-up of aortic regurgitation. Computed tomography and magnetic resonance imaging showed no suggestive signs of malignant tumors, and thrombus or myxoma was initially suspected. However, an initial transthoracic and transesophageal echocardiogram did not exclude the possibility of a malignant tumor attached to the wall of the pulmonary artery. Considering the embolization risk, we opted to perform tumorectomy, in which additional surgical procedures could then be conducted if intraoperative diagnosis showed a malignant tumor. Indeed, intraoperative findings showed the tumoral mass attached on the left semilunar cusp of the pulmonary valve, and intraoperative diagnosis of the tumor showed no malignancy. Planned tumorectomy was performed concomitantly with AVR. The pathologic examination of the removed tumor confirmed the diagnosis of PFE. Her postoperative course was uneventful without any sign of recurrence. CONCLUSION: This case highlights the difficulty of accurate diagnostic imaging and provides valuable insight into a successful surgical treatment of pulmonary valve PFE without any complications.

Effects of Glycyrrhizic Acid in Licorice on Prolongation of Murine Cardiac Allograft Survival.

Recent evidence has pointed to the promising benefits of using specific immunosuppressive herbal compounds to prolong transplant allograft survival. In this study, we investigated the effects of glycyrrhizic acid (GA), a major component of licorice, in a model of murine heart transplantation. CBA (H2k) mice were transplanted with a fully-MHC mismatched C57BL/6 (H2b) heart allograft and subsequently received daily intraperitoneal administration of normal saline or 0.02, 0.2, or 2.0 mg/d of GA for 7 consecutive days. Untreated CBA recipients, with a median survival time (MST) of 7 days, and groups receiving 0.02mg/d (MST, 8 days) or 0.2mg/d (MST, 9 days) of GA acutely rejected C57BL/6 cardiac allografts. But mice treated with 2.0 mg/d of GA demonstrated significant prolongation of allografts (MST, 23 days). Histologic studies showed that cardiac allografts from GA-treated CBA recipients had preserved graft and vessel structure. Moreover, flow cytometric study showed that the percentage of CD4+CD25+Foxp3+ cell (regulatory T cell [Treg]) populations were increased in GA-treated CBA recipients. In a mixed leukocyte culture, splenocytes from GA-treated mice demonstrated suppressed allo-proliferation, in which interleukin (IL)-2 and interferon gamma production were downregulated and IL-10 secretion was upregulated. In conclusion, GA may be a novel promising therapeutic agent to prolong cardiac allograft survival through direct anti-inflammatory effects and induction of Treg populations.

Saireito (TJ-114) Suppressed Donor-Specific Antibody Through Immunomodulatory Effects and Regulatory T Cell Induction in a Murine Heart Transplant Model.

Saireito (Tsumura Japan [TJ]-114) could induce long-term cardiac allograft survival through the generation of CD4+CD25+Foxp3+ cells (regulatory T cells, Tregs). However, little is known regarding the effects of TJ-114 on the suppression of donor-specific antibody (DSA). Therefore, we aimed to further investigate the suppressive properties of TJ-114 and its effects on DSA production in a murine cardiac allograft model. CBA mice underwent transplantation of C57BL/6 hearts and were subsequently administered TJ-114 (2g/kg/d) from the day of transplantation until 7 days afterward. TJ-114-treated recipients demonstrated upregulation of splenic Tregs and suppressed DSA production at postoperative day 10 relative to untreated controls. This effect was sustained at postoperative day 20 even when TJ-114 administration was stopped at day 7. To then investigate the involvement of Tregs in the suppression of DSA production, anti-interleukin-2 receptor alpha antibody (PC-61) was administered to deplete Treg populations in TJ-114-treated CBA recipients on postoperative days 0, 3, 6, and 9 or 20, 23, and 26. At day 10, CBA recipients that received PC-61 with TJ-114 demonstrated suppression of DSA production similar to those receiving only TJ-114. Nonetheless, when mice were treated with PC-61 at days 20, 23, and 26, DSA levels gradually increased to levels comparable to those of untreated mice by day 29, suggesting that Tregs are necessary to sustain the suppression of DSA once the effects of TJ-114 have subsided. Taken together, TJ-114 may be a promising therapeutic strategy to prolong allograft survival through its combined immunosuppressive effects in inducing Tregs and suppressing DSA production.

Evaluation of Cardiac Graft Function by Echocardiography in Mice.

BACKGROUND: Generally, graft function in the murine cardiac allograft transplant model is assessed daily by palpating the heart for evidence of contraction. To our knowledge, few reports have investigated the correlation of cardiac graft function using echocardiography and immunohistochemical studies. In this study, we investigated the efficacy of echocardiographic and histologic evaluation of alloimmune responses in the acute phase of murine cardiac allografts. METHODS: Fully vascularized heterotopic hearts from CBA (allogeneic group) or C57BL/6 (syngeneic group) donors were transplanted into C57BL/6 recipients using microsurgical techniques. Fluctuations in heart rate, left ventricular ejection fraction (LVEF), left ventricular functional shortening (LVFS), right ventricular outflow tract maximal systolic velocity (RVOT Vmax), and RVOT velocity time integral (RVOT VTI) were evaluated on postoperative days (PODs) 1, 3, 5, 7, and 9 after transplantation using an ultrasonic device. Histologic studies were also performed. RESULTS: The syngeneic group did not show a complete cessation of heartbeat or deterioration of cardiac function. CBA recipients in the allogeneic group rejected cardiac allografts on POD 9 after grafting. LVEF and LVFS in the allogeneic group gradually decreased on POD 9. Consistent with the time-course echocardiographic evaluation, histologic studies showed gradual atrophy of the left ventricle. In contrast, RVOT Vmax and RVOT VTI in the allogeneic group were not significantly different during the observation period. Additionally, the thickness of the right ventricular wall did not change until POD 7. CONCLUSION: The present findings suggested that echocardiography may help to evaluate time-course murine cardiac graft function through left ventricular parameters such as LVEF and LVFS.

Effects of Each Domain in Recombinant Human Soluble Thrombomodulin on Prolongation of Murine Cardiac Allograft Survival.

Thrombomodulin is used to manage disseminated intravascular coagulation. In our murine heart transplantation model, the administration of recombinant human soluble thrombomodulin (rTM) could induce the prolongation of cardiac allograft survival. However, there are limited data on the graft protective effects of each r domain (D1, D2, and D3). In this study, we investigated the effects of each domain of rTM on alloimmune responses in a murine model of cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA recipients using microsurgical techniques. CBA mice that underwent transplantation of C57BL/6 cardiac allografts were assigned to 4 groups: no treatment and each domain-exposed group. The dosage of each domain was determined based on our previous experiments. Flow cytometry and histologic studies were performed to determine whether Foxp3+ regulatory T cells were generated. Untreated and D2-exposed CBA recipients acutely rejected C57BL/6 cardiac allografts within 9 days. Administration of D3 resulted in modest prolongation of allograft survival, and administration of D1 significantly prolonged allograft survival. Histologic studies showed that myocardial damage of allografts from D1- and D3-exposed CBA recipients was controlled compared with that of untreated recipients. In particular, the CD4+CD25+Foxp3+ cell population in the splenocytes of D1-exposed CBA recipients was increased. In conclusion, D1 in rTM could help prolong cardiac allograft survival through regulatory T cell induction and graft protective effects.

Two-Year Results of a Multicenter Prospective Observational Study of the Zenith Spiral-Z Limb Deployed in the External Iliac Artery During Endovascular Aneurysm Repair.

BACKGROUND: Limited data is available on the use of a polyester graft limb with a helical stent configuration deployed in the external iliac artery (EIA) during endovascular aneurysm repair (EVAR), so we prospectively analyzed the efficacy of the Zenith Spiral-Z limb deployed in the EIA.Methods and Results:Patients undergoing EVAR using a Zenith stent-graft and Spiral-Z limb deployed in the EIA were prospectively registered in 24 Japanese institutions from June 2017 to November 2017. In total, 65 patients (74 limbs) (mean age: 77.1±8.0 years, 87.7% men, mean abdominal aortic aneurysm (AAA) diameter: 51.9±7.2 mm, mean iliac artery aneurysm (IAA) diameter: 38.3±10.0 mm) were registered and followed up. The most common reason for deployment in the EIA was a common IAA (43 limbs, 58.1%), and 8 limbs (10.8%) had a bare nitinol stent placed at the Spiral-Z limb. A total of 61 patients (70 limbs) completed a 24-month follow-up. There were 2 Spiral-Z limb stenoses and 1 occlusion, leading to a primary patency of 95.5% and a secondary patency of 100%, at 24 months. Buttock claudication occurred in 24.3% of the limbs treated at 1 month but decreased to 4.3% at 24 months. CONCLUSIONS: Our multicenter prospective study showed that Spiral-Z limb deployed in the EIA was associated with satisfactory results and seems to be a durable option, even in the era of iliac branch devices.

Primary malignant pericardial mesothelioma presenting with cardiac tamponade.

INTRODUCTION: Primary malignant pericardial mesothelioma is a rare tumor that is very difficult to diagnose. Furthermore, it is a lethal disease, because patients usually have progressed at the time of referral. PRESENTATION OF THE CASE: We report a 44-year-old man with primary malignant pericardial mesothelioma. He was referred to our hospital for the diagnosis and treatment of a massive pericardial effusion and huge tumor. Pericardiocentesis was performed, but we could not obtain definitive diagnosis, and the cardiac tamponade continued along with the signs/symptoms. He required surgical intervention for the diagnosis and treatment. After surgery, his signs/symptoms improved. He received adjuvant therapy, although he died 7 months after surgery. DISCUSSION: Primary malignant pericardial mesothelioma is a rare tumor. The most common signs and symptoms are related to constriction of the heart by the tumor and/or effusion. Even if the pericardial fluid specimen obtained by pericardiocentesis is negative for malignant cells, primary malignant pericardial mesothelioma should be included in the differential diagnosis. Because the malignancy is usually advanced at the time of diagnosis, it has been difficult to cure. Radiation and chemotherapy have been used in addition to surgery, but have been minimally effective. CONCLUSION: The outcome of our patient with pericardial malignant mesothelioma was dismal. The indications for surgical intervention should be carefully considered except for critical cases requiring alleviation of immediate life-threating conditions.

Surgical Treatment Strategy with Combined Cardiopulmonary Bypass for Renal Cell Carcinoma with Tumor Embolism Developed in Inferior Vena Cava.

OBJECTIVE: Renal cell carcinoma (RCC) with tumor thrombus in the inferior vena cava (IVC) presents surgeons with a technical intraoperative challenge because of the need for aggressive surgical management. In this study, we describe our method for surgical management with cardiopulmonary bypass (CPB) and investigate the long-term outcomes of RCC patients with and without CPB. METHODS: Fifteen patients with RCC underwent nephrectomy and IVC thrombectomy from May 2011 to December 2017. We retrospectively reviewed and analyzed the clinical course of all patients. Novick classification was used to assess the level of tumor thrombus extension into the IVC. Patient characteristics, surgical procedures, and postoperative outcome data in both groups were collected. RESULTS: Twelve patients were male and 3 were female, with an average age of 62.9 ± 10.9 years (range 46 to 82). The average operative times were 824 ± 335 minutes in the patients with CPB and 646 ± 162 minutes in those without CPB (P = .17). The average amount of intraoperative bleeding was 2125 ± 1315 ml in the patients with CPB and 3333 ± 1431 ml in those without CPB (P = .14). The same tendency was observed in patients of Novick levels 3 and 4. The mean observation period was 1061.4 days. No 30-day mortality was noted. There was no significant difference in all-cause survival between the patients with CPB and those without. CONCLUSIONS: We conclude that surgical management with CPB and circulatory arrest may be a viable and safe method of treatment for RCC patients.

Thoracic aortic endografts used to resect the left subclavian artery infiltrated by malignant tumours.

Endograft placement is a minimally invasive procedure used to repair thoracic aortic aneurysms. This technique is used for treating aneurysms and aortic dissections or ruptures, but it can also be applied for the resection of malignant tumours with vascular invasion. We describe the successful use of the thoracic endovascular aortic repair technique to remove a malignant tumour infiltrating the left subclavian artery in a 50-year-old man. The resection of the left subclavian artery infiltrated by thoracic malignant tumours may require temporary cardiopulmonary bypass, direct clamping of the aorta or extracorporeal circulation techniques. However, the off-label use of thoracic endovascular aortic repair avoids the need for these high-risk surgical techniques. After the surgical removal of the mass and combined aortic resection without complications, the patient was eligible to undergo chemotherapy/radiotherapy, thus improving his prognosis.

Surgical treatment of a huge hepatic artery aneurysm without revascularization-Case Report.

INTRODUCTION: Hepatic artery aneurysms (HAA) are rare and life-threatening. PRESENTATION OF CASE: We report a case of a 68-year-old man with a huge HAA diagnosed incidentally. Computed tomography showed a huge HAA (67-84 mm diameter). The patient underwent aneurysm resection and ligation of the common and proper hepatic arteries via laparotomy. Revascularization was not performed because intraoperative ultrasound showed pulsatile inflow to the left hepatic lobe. Postoperative cholecystitis and hepatic infarction were temporarily observed. Two months after the previous discharge, cholecystectomy was performed. DISCUSSION: A diameter ≥5 cm of HAA is thought to be rare in arterial aneurysm diseases. There is no consensus in the treatment policy and treatment is selected according to the patient's condition. In this case, we selected open surgery for this patient instead of endovascular surgery due to rupture risks, irregularity and narrowness of vessel structure, and prolonged irradiation-time. If revascularization is not performed at the time of resection, open surgery with cholecystectomy is capable of preventing postoperative cholangitis after resection of HAA, and should be taken into account even if collateral circulation can be confirmed. CONCLUSION: This case highlights the difficulty of managing HAA and provides insight into a successful surgical treatment of HAA without complete revascularization.

A case of an elderly man who required repeated repair of a ventricular septal defect and tricuspid rupture after blunt chest trauma.

Several cases of traumatic ventricular septal defect (VSD) have been reported. However, traumatic VSD complicated by tricuspid rupture is rare. We report a case of traumatic VSD with tricuspid rupture who required repeated repair of both conditions. A 69-year-old man was transferred to our hospital for emergent surgical repair of traumatic VSD and tricuspid rupture. Although emergent repair was performed, a new left-to-right shunt and moderate tricuspid regurgitation appeared during his postoperative course. A reoperation was performed 4 months after the first operation. The borders of the defect were very fibrotic and strong compared with those in the first operation. Surgical treatment of traumatic VSD should be postponed in hemodynamically stable patients. When emergent repair is performed, careful follow-up is necessary to diagnose new VSD.

Combined Aortic Resection and Stent Graft Insertion for Local Recurrence of Metastatic Lung Carcinoma Following Stereotactic Radiotherapy: A Case Report.

Stereotactic radiotherapy (SRT) is a useful treatment for malignant ling tumors. However, SRT is associated with complications such as high local recurrence rate and radiation-induced lung injury. Herein, we report a case of combined aortic resection for after SRT. An 82-year-old man underwent SRT for the metastatic lung carcinoma of rectal cancer at left lower lobe. Three years later, chest computed tomography showed local recurrence at the site of radiotherapy, with suspected invasion of the descending aorta. Thoracotomy was performed after metastatic lung carcinoma interpolation of a stent graft in the descending aorta. Because the tumor firmly adhered to the aorta, left lower lung lobe and aortic wall resection was performed. Pathological findings revealed fibrous hypertrophy and adhesion between the visceral pleura and aorta. As shown in our case, combined aortic resection and stent graft insertion is an effective minimally invasive and safe treatment for SRT-induced tissue damage.

Combination of paeoniae radix and cnidii rhizoma prolonged survival of fully mismatched cardiac allografts and generated regulatory cells in mice.

In previous studies, we have demonstrated that Tokishakuyakusan (TJ-23) can prolong the survival of allogeneic cardiac grafts and induce regulatory T cells. In this study we investigated the effects of Paeoniae radix and Cnidii rhizoma, two components of TJ-23, on alloimmune responses in a murine cardiac transplantation model and whether the two agents have synergistic effect. CBA mice underwent transplantation of a C57BL/6 heart and received oral administration of 2 g/kg/day of Paeoniae radix, Cnidii rhizoma, or the mixture of two agents from the day of transplantation until 7 days afterward. Naïve CBA mice rejected C57BL/6 cardiac graft acutely (median survival time (MST): 7 days). Paeoniae radix and Cnidii rhizoma prolonged C57BL/6 allograft survival (MSTs: 13.5 and 15.5 days, resp.). However, the mixture of two agents prolonged C57BL/6 allograft survival indefinitely (MST > 100 days). Secondary CBA recipients given whole splenocytes from primary combination-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MST: 33 days). Flow cytometry studies showed that the CD4(+)CD25(+)Foxp3(+) regulatory cell population was increased in combination-treated recipients. Combination of Paeoniae radix and Cnidii rhizoma induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4(+)CD25(+)Foxp3(+) regulatory cells in our model.

An agonistic anti-BTLA mAb (3C10) induced generation of IL-10-dependent regulatory CD4+ T cells and prolongation of murine cardiac allograft.

BACKGROUND: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmunity and may potentially play an important role in allograft tolerance. This study investigated the effect of an agonistic anti-BTLA mAb (3C10) in the fully major histocompatibility complex-mismatched murine cardiac transplantation. METHODS: CBA mice underwent transplantation of C57BL/6 hearts and received one dose of 3C10 on the day of transplantation (day 0) or four doses of 3C10 on day 0, 3, 6, and 9. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Moreover, to confirm the requirement for regulatory T cell and Th-2 cytokines, anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) was administered to a 3C10-treated CBA recipient. RESULTS: CBA mice treated with one and four doses of 3C10 prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or CD4 cells from primary 3C10-treated CBA recipients had significantly prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Also, flow cytometry studies showed an increased CD4CD25Foxp3 cell population in 3C10-treated mice. Additionally, IL-2 and interferon-γ production were suppressed in 3C10-treated mice, and IL-4 and IL-10 from 3C10-treated CBA mice increased. Moreover, 3C10 directly suppressed alloproliferation in a mixed leukocyte culture. However, administration of PC-61 or JES-2A5 clearly attenuated prolonged survival of 3C10-treated mice (MSTs, 15.5 and 13.5 days, respectively). CONCLUSION: 3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10-dependent regulatory CD4 T cells.