IL-33 drives the production of mouse regulatory T cells with enhanced in vivo suppressive activity in skin transplantation.

Regulatory T cells (Tregs) are crucial mediators of immune homeostasis with the ability to modulate allogeneic response and control transplant rejection. Although Treg-based cell therapies have shown immense promise, methods to optimize current strategies are critical for successful implementation within the clinic. IL-33 is a cytokine with pleiotropic properties and effects on Treg function and development. In this study, we explored the unique properties of Treg populations activated through the IL-33/ST2 pathway, aiming to exploit their tolerogenic properties for cell therapy. We show that treatment with exogenous IL-33 results in a generalized downregulation of genes critical to T cell biology together with an upregulation of Treg-associated genes. Tregs that develop in response to IL-33 upregulate critical Treg-associated markers, yet without developing enhanced in vitro suppressive capacity. Conversely, these Tregs display potent regulatory activity in vivo, promoting long-term skin allograft survival in a stringent transplantation model. Detailed transcriptomic and immunophenotypic analyses of IL-33-expanded Tregs reveal an enhancement in graft-homing chemokine receptors, which may be partly responsible for their superior in vivo activity that is not reflected in vitro. IL-33 treatment is therefore an attractive adjunctive strategy for patients receiving Treg cell therapeutics.

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.

Treadmill exercise induces murine cardiac allograft survival and generates regulatory T cell.

Exercise therapy has been associated with improvement in functional capacity and quality of life. The role of exercise therapy in heart transplant recipients is of great interest for the transplant society, although concerning the effect of exercise therapy, there is little knowledge at present. We analyzed the effects of exercise on alloimmune responses in murine cardiac allograft transplantation. CBA mice (H2(k) ) underwent transplantation of C57Bl/6 (H2(b) ) hearts and exercised on a treadmill. Untreated CBA recipients rejected C57Bl/6 cardiac grafts acutely (median survival time [MST], 7 days). CBA recipients treated with treadmill for 1 week after transplantation, and for 1 week both before and after transplantation prolonged allograft survivals (MSTs, 35 and 18 days, respectively). However, treadmill exercise recipients for 1 week before transplantation were not effective to allograft survival (MST, 8 days). Adoptive transfer of whole splenocytes and CD4(+) cells from treadmill exercise recipients significantly prolonged allograft survival in naive secondary recipients (MSTs, 30 and 52 days, respectively), suggesting that regulatory cells was generated after treadmill exercise. Moreover, flow cytometry studies showed that CD4(+) CD25(+) Foxp3(+) cell population increased in treadmill exercise recipients. Therefore, postoperative but not pre-operative exercise could induce prolongation of survival of fully allogeneic cardiac allografts and generate CD4(+) CD25(+) Foxp3(+) regulatory T cells.

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.

Investigating the early diagnosis of pancreatic cancer by surveillance of patients with "K-sign" of the pancreas by computed tomography: A prospective study.

BACKGROUND: We previously conducted a retrospective study investigating pancreatic morphological abnormalities that lead to early diagnosis of pancreatic cancer (PC) using computed tomography (CT). We reviewed 41 of 308 PC patients between 2011 and 2017 who had previously undergone CT to look for morphological changes leading to cancer development. In 24 patients (58.5%), a K-shaped constriction of the pancreas ("K-sign") was observed before the appearance of cancer. This study aimed to investigate whether an early PC diagnosis is possible by prospective CT follow-up of patients with the K-sign. METHODS: We investigated PC development through prospective surveillance of patients exhibiting K-signs identified on CT. RESULTS: Of approximately 87 000 CT scans performed between April 2019 and August 2022, the K-sign was observed in 54 patients. A total of 30 patients provided informed consent and were subsequently monitored using CT. Five patients (16.7%) were diagnosed with PC and underwent surgery after 3-24 months follow-up. Pathologically, four of five patients (80%) were diagnosed with early-stage pancreatic cancer (stage 0-IA). All patients exhibited defects in acinar structure, fibrous tissue, fat replacement, and inflammatory cells, suggesting their potential involvement in PC development. CONCLUSION: The detection and surveillance of the K-sign may be helpful for early PC diagnosis.

Graft protective effects and donor-specific antibody suppression by CD4+CD25+Foxp3+ regulatory T cell induced by HMG-CoA reductase inhibitor rosuvastatin in a murine heart transplant model.

BACKGROUND: We previously demonstrated that the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (statins) play an important role in the regulation of alloimmune responses. However, little is known regarding the effects of statin on allograft protection or donor-specific antibodies (DSA). In this study, we investigated the graft-protective and immunomodulatory effects of rosuvastatin in a model of fully major histocompatibility complex-mismatched murine cardiac allograft transplantation. METHODS: CBA mice underwent transplantation of C57BL/6 (B6) hearts and received 50 and 500 µg/kg/day of rosuvastatin from the day of transplantation until seven days after the completion of transplantation. To confirm the requirement for regulatory T cells (Tregs), we administered an anti-interleukin-2 receptor alpha antibody (PC-61) to rosuvastatin-treated CBA recipients. Additionally, histological and fluorescent staining, cell proliferation analysis, flow cytometry, and DSA measurements were performed. RESULTS: CBA recipients with no treatment rejected B6 cardiac graft acutely (median survival time [MST], 7 days). CBA mice treated with 500 µg/kg/day of rosuvastatin prolonged allograft survival (MSTs, 77 days). Fluorescent staining studies showed that rosuvastatin-treated recipients had strong aggregation of CD4+Foxp3+ cells in the myocardium and around the coronary arteries of cardiac allografts two weeks after grafting. Flow cytometry studies performed two weeks after transplantation showed an increased number of splenic CD4+CD25+Foxp3+ T cells in rosuvastatin-treated recipients. The addition of rosuvastatin to mixed leukocyte cultures suppressed cell proliferation by increasing the number of CD4+CD25+Foxp3+ Tregs. Additionally, Tregs suppressed DSA production in rosuvastatin-treated recipients. CONCLUSION: Rosuvastatin treatment may be a complementary graft-protective strategy for suppressing DSA production in the acute phase, driven by the promotion of splenic and graft-infiltrating CD4+CD25+Foxp3+ Tregs.

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.

Effects of Japanese herbal medicine Sairei-to on murine experimental autoimmune uveitis.

PURPOSE: It has been suggested thatSairei-to (TJ114), a traditional Japanese herbal medicine, has immunomodulatory activities. To evaluate the effects of TJ114 on uveitis, we examined the effectiveness of oral administration in a murine model of experimental autoimmune uveitis (EAU). METHODS: Murine EAU was induced by subcutaneous injection of human inter-photoreceptor retinoid-binding protein (IRBP) peptide mixed with complete Freund's adjuvant. In the TJ114-treated group, 2 g/kg was administrated orally from 0 to 20 days after immunization. Clinical scoring, histopathological scoring of EAU, cell proliferation, cytokine assessment, and adoptive transfer experiment of splenic T cells into naïve mice were performed. RESULTS: EAU development occurred in 32 of 38 mice (86 %) in the untreated group and 12 of 33 (36 %) in the TJ114-treated group. The clinical scores for EAU in the vehicle-treated and TJ114-treated groups were 1.56 ± 1.65 and 0.59 ± 0.63 respectively, at 14 days after immunization (p < 0.01, Mann-Whitney U-test), and 2.26 ± 1.56 and 0.75 ± 1.31 respectively at 21 days (p < 0.001, Mann-Whitney U-test), while the histopathological scores at 21 days were 1.47 ± 1.42 and 0.54 ± 0.84 respectively (p < 0.01, Mann-Whitney U-test). Interferon (IFN)-γ and tumor necrosis factor (TNF)-α production by cervical lymph node cells obtained from the TJ114-treated group were significantly reduced as compared with those from the vehicle-treated group (p < 0.01, Student's unpaired t-test). Moreover, the levels of C-C motif chemokine 2 (CCL2) and IFN-γ were significantly reduced in splenocytes of TJ114-treated mice as compared with the vehicle-treated group (p < 0.01, Student's unpaired t-test). Mice that received adoptive transfer of splenic T cells from TJ114-treated EAU mice caused significantly lower severity of EAU compared to those that received from vehicle-treated EAU mice. CONCLUSION: Oral administration of TJ114 has an inhibitory effect on a murine model of EAU, possibly via reduction in cytokine production by helper type-1 T cells.

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.

Danazol induces prolonged survival of fully allogeneic cardiac grafts and maintains the generation of regulatory CD4(+) cells in mice.

Danazol, a derivative of testosterone, is useful for treatment of endometriosis as well as pretreatment for in vitro fertilization and embryo transfer, although its mechanisms of action are unclear. The aim of this study was to investigate the effect of danazol on alloimmune responses in murine heart transplantation. CBA male mice (H2(k) ) underwent transplantation of C57BL/6 male (H2(b) ) hearts and received a single dose of danazol (0.4, 1.2 or 4mg/kg/day) by intraperitoneal injection on the day of transplantation and for 6days thereafter. An adoptive transfer study was performed to determine whether regulatory cells were generated. The median survival time (MST) of allografts in danazol-treated (1.2 and 4mg/kg/day) mice was 28 and 63days, respectively, compared with 7days in untreated mice. Moreover, secondary CBA recipients given whole splenocytes or CD4(+) cells from primary danazol-treated (4mg/kg/day) CBA recipients 30days after transplantation had prolonged allograft survival (MSTs, 29 and 60days, respectively). Cell proliferation, interleukin (IL)-2 and interferon-γ were suppressed in danazol-treated mice, whereas IL-4 and IL-10 were up-regulated. Moreover, danazol directly suppressed allo-proliferation in a mixed leukocyte culture. Flow cytometry showed an increased CD4(+) CD25(+) Foxp3(+) cell population in splenocytes from danazol-treated mice. Danazol prolongs cardiac allograft survival and generates regulatory CD4(+) cells.

Inchingorei-san (TJ-117) and Artemisiae Capillaris Herba Induced Prolonged Survival of Fully Mismatched Cardiac Allografts and Generated Regulatory Cells in Mice.

We investigated Inchingorei-san (TJ-117), a 6-component Japanese herbal medicine, on alloimmune responses in murine cardiac allograft transplantation. CBA mice underwent transplantation of a C57BL/6 (B6) heart and received oral administration of TJ-117 or each component of TJ-117 from the day of transplantation until 7 days afterward. Naive CBA mice rejected B6 cardiac grafts acutely (median survival time (MST), 7 days). CBA recipients given 1 g/kg/day of TJ-117 had prolonged B6 allograft survival (MST, 37 days). Moreover, given 1 g/kg/day of Artemisiae Capillaris Herba (ACH), one component of TJ-117, indefinitely prolonged B6 allograft survival (MST, >100 days). However, other five components of TJ-117 were less effective than TJ-117 and ACH. Secondary CBA recipients given whole splenocytes, CD4(+), and CD4(+)CD25(+) cells from primary ACH-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MSTs, 57, >100, and >100 days, resp.). Flow cytometry studies showed that the CD4(+)CD25(+)Foxp3(+) regulatory cell population was increased in transplant recipients given ACH. Cell proliferation, interleukin-2, and interferon-γ were suppressed in ACH-treated mice, whereas interleukin-4 and interleukin-10 were upregulated. In conclusion, ACH, one component of TJ-117, as well as TJ-117 induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4(+)CD25(+)Foxp3(+) regulatory cells.

Successful cases of percutaneous left ventricular assist device "Impella" to fulminant myocarditis.

BACKGROUND: Fulminant myocarditis (FM) is a form of severe inflammatory carditis with rapidly developing acute heart failure. CASE PRESENTATION: We report three cases of successful intensive treatment by Impella of FM without any complications. In all cases, impairment of microcirculation as measured by blood lactate level and the hemodynamic value as indicated by cardiac index were improved within 24-48 h and 7 days after Impella implantation, respectively. Interestingly, our data also suggested that treatment by Impella CP or 5.0 may lead to faster recovery of microcirculation and cardiac function than treatment by Impella 2.5. CONCLUSION: Our findings demonstrate that the appropriate selection of Impella devices guided by body surface area measurements may help to improve clinical outcomes of severe heart failure including FM.

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.

The "K-Sign"-A Novel CT Finding Suggestive before the Appearance of Pancreatic Cancer.

Pancreatic invasive ductal adenocarcinoma (PDAC) has a poor prognosis, and the detection of PDAC during the early stage is thought to improve prognosis. In this study, we retrospectively investigated pancreatic morphological abnormalities that lead to the early diagnosis of PDAC with computed tomography (CT) imaging. In total, 41 out of 308 patients diagnosed with pancreatic cancer between 2011 and 2017 in our institution were enrolled. As a control group for the group with pancreatic cancer, 4277 patients without pancreato-biliary diseases were enrolled. We retrospectively reviewed and analyzed the clinical data including patient characteristics, the clinical course and preoperative CT imaging with pancreatic morphological features. Out of 41 patients, 24 patients (58.5%) showed local K-shaped constriction of the pancreatic parenchyma "K-sign" on preoperative CT images. Eight patients (19.5%) showed localized fatty change. Out of 4277 control patients, seven patients (0.16%) showed K-sign. "K-sign" may be used for the early diagnosis of PDAC by CT imaging.

Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo.

Humanized immune system (HIS) mouse models are useful tools for the in vivo investigation of human hematopoiesis. However, the majority of HIS models currently in use are biased towards lymphocyte development and fail to support long-term multilineage leucocytes and erythrocytes. Those that achieve successful multilineage reconstitution often require preconditioning steps which are expensive, cause animal morbidity, are technically demanding, and poorly reproducible. In this study, we address this challenge by using HSPC-NBSGW mice, in which NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice are engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs) without the need for preconditioning by sublethal irradiation. These HSPCs are enriched in long-term hematopoietic stem cells (LT-HSCs), while NBSGW mice are permissive to human hematopoietic stem cell (HSC) engraftment, thus reducing the cell number required for successful HIS development. B cells reconstitute with the greatest efficiency, including mature B cells capable of class-switching following allogeneic stimulation and, within lymphoid organs and peripheral blood, T cells at a spectrum of stages of maturation. In the thymus, human thymocytes are identified at all major stages of development. Phenotypically distinct subsets of myeloid cells, including dendritic cells and mature monocytes, engraft to a variable degree in the bone marrow and spleen, and circulate in peripheral blood. Finally, we observe human erythrocytes which persist in the periphery at high levels following macrophage clearance. The HSPC-NBSGW model therefore provides a useful platform for the study of human hematological and immunological processes and pathologies.