Prolongation of survival of fully allogeneic cardiac grafts and generation of regulatory cells by a histamine receptor 2 antagonist.

BACKGROUND: The effects of histamine on immunologic responses via the histamine receptor 2 (HR2) have been studied, but few investigations explored the immunomodulatory role of histamine in vivo. We examined whether the HR2 antagonist ranitidine affects the alloimmune response in a murine model of cardiac transplantation. METHODS: CBA (H-2k) recipients were given no treatment or one intravenous injection of ranitidine on the day of transplantation of a heart from C57BL/10 (H-2b) donors. Survival of the allografts was recorded. The effect of the ranitidine treatment on cell proliferation and cytokine production was assessed by mixed leukocyte culture and enzyme-linked immunosorbent assays. An adoptive transfer study was conducted to determine whether regulatory cells were generated. The effect on graft survival of adding FK506 to the ranitidine treatment was also examined. RESULTS: CBA recipients given ranitidine (60 mg/kg) had prolonged graft survival (median survival time [MST], 87 days). Ranitidine treatment also suppressed the proliferation of splenocytes and production of interleukin (IL)-2 and up-regulated IL-10 production. Adoptive transfer of splenocytes and CD4 cells from ranitidine-treated allograft recipients induced significant prolongation of allograft survival in naive secondary recipients (MST, 71 and >100 days, respectively). CBA recipients given both ranitidine and FK506 (0.1 mg/kg/day for 14 days) had indefinite survival of cardiac allografts (MST, >100 days). CBA recipients treated with FK506 alone rejected the allografts (MST, 27 days). CONCLUSION: In our model, ranitidine treatment induced significantly prolonged survival of fully allogeneic cardiac grafts, generated CD4 regulatory cells, and indefinite survival when combined with FK506 (0.1 mg/kg/day).

A case of ectopic hepatocellular carcinoma in the jejunum.

We describe the case of a 72 year-old man with a huge tumor in his lower abdomen and extremely high serum alpha-fetoprotein levels (99,100 ng/ml). The patient had no risk factors for hepatocellular carcinoma (HCC) or liver disease. Computed tomography, magnetic resonance imaging, and hepatic angiography detected no tumors in the liver before surgery. The arteries feeding the tumor arose from the superior mesenteric artery, but were not recognized on celiac angiography. Histologically, the tumor cells had features of HCC. Immunohistochemical staining revealed that the tumor cells were positive for AFP and the hepatocyte paraffin 1 monoclonal antibody. Furthermore, the tumor cells were strongly positive for cytokeratin 8 and cytokeratin 18, which are usually expressed on hepatocytes in HCC, and negative for both cytokeratin 7 and cytokeratin 20, which are not usually expressed in HCC. Hence, the tumor was diagnosed as an ectopic HCC that possibly developed from ectopic liver tissue in the jejunum. Approximately 2 months after the operation, transarterial chemoembolization was performed for liver metastasis from this tumor. One year after the transarterial chemoembolization procedure, the patient remains well with no evidence of a recurrent tumor or serum AFP elevation.

Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride.

BACKGROUND: At initiation of the immunologic response, platelets rapidly release chemical mediators such as serotonin (5-hydroxytryptamine, [5-HT]) and cytokines. Sarpogrelate hydrochloride (SH), a selective 5-HT2-receptor antagonist, is used to treat patients with peripheral arterial disease. We investigated the effect of SH on the alloimmune response in a murine cardiac transplantation model. METHODS: CBA mice underwent transplantation of a C57BL/10 heart and received a short course of SH treatment. Survival of the allograft was recorded. An adoptive transfer study was performed to determine whether regulatory cells were generated. Immunohistochemistry studies of intercellular adhesion molecule 1 (ICAM-1), histological, cell-proliferation, and cytokine assessments were performed. RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST], 8 days). In mice given 10 mg/kg of SH, all allografts survived indefinitely (MST, >100 days); these mice also had significantly prolonged survival of donor-specific skin grafts but acute rejection of third-party skin grafts. Secondary CBA recipients given not only whole but also CD4 splenocytes from primary SH-treated CBA recipients with C57BL/10 cardiac allograft had indefinite survival of C57BL/10 hearts (MST, >100 days). SH inhibited upregulation of ICAM-1 on endothelial cells in the allografts. Graft acceptance and hyporesponsiveness were confirmed by the histological and cell-proliferation studies, respectively. Production of interleukin-4 and interleukin-10 from splenocytes of SH-treated transplant recipients increased compared to that from splenocytes of untreated recipients. CONCLUSION: SH induced indefinite survival of fully allogeneic cardiac allografts, generated CD4 regulatory cells, inhibited ICAM-1 expression in the allografts, and upregulated IL-4 and IL-10 production.

[A case of advanced gastric cancer with peritoneal dissemination responding remarkably to TS-1/CDDP combination chemotherapy].

A 57-year-old woman visited a physician with complaints of anorexia and pollakiuria. Because a pelvic tumor and ascites were detected, she was referred to our department. Douglas pouch puncture revealed adenocarcinoma cells. Further examination showed an advanced gastric cancer with peritoneal dissemination. The cancer was judged to be unresectable. Chemotherapy with a combination of TS-1 and CDDP was performed before the operation. After 2 courses of the chemotherapy, her complaints disappeared, although abdominal CT confirmed remaining peritoneal dissemination. After 7 courses of chemotherapy, abdominal CT showed that the peritoneal dissemination had disappeared. Total gastrectomy and lymph node dissection were performed. Histological findings of the stomach revealed complete disappearance of cancer cells in the stomach and the regional lymph nodes. We confirmed that the TS-1/CDDP therapy resulted in a complete response to advanced gastric cancer and peritoneal dissemination. We recommend that chemotherapy be continued until the peritoneal dissemination disappears.

Effects of immunosuppressants on induction of regulatory cells after intratracheal delivery of alloantigen.

BACKGROUND: We previously reported that intratracheal delivery (ITD) of alloantigen generated regulatory cells in mice. Here, we examined the effect of various doses of conventional immunosuppressants (FK506, cyclosporine A, azathioprine, mycophenolate mofetil, and rapamycin) on inducing regulatory cells in our model. METHODS: CBA mice (primary recipients) were given C57BL/6 splenocytes by ITD and either no additional treatment or various doses of an immunosuppressant. Seven days later, splenocytes from these mice were adoptively transferred into naive secondary CBA recipients that underwent C57BL/6 cardiac grafting the same day. RESULTS: Adoptive transfer from primary recipients given ITD of splenocytes alone induced prolonged allograft survival in secondary recipients (median survival time [MST], 50 days), suggesting that regulatory cells were generated. When ITD of alloantigen was combined with daily administration of 0.1 mg/kg FK506 or 0.2 mg/kg rapamycin, graft survival was similarly prolonged (MST 55 and 50 days, respectively). When combined with 20 or 40 mg/kg MMF or 0.4 mg/kg rapamycin, the majority of recipients demonstrated indefinite survival (MST, >100 days in all groups). When ITD of alloantigen was combined with 0.3, 0.5, or 1.0 mg/kg FK506; 5, 10, or 25 mg/kg cyclosporine A; or 1.0 or 2.0 mg/kg azathioprine, allografts were rejected acutely (MST 7-13 days). CONCLUSION: Generation of regulatory cells by ITD of alloantigen was facilitated by mycophenolate mofetil and high doses of rapamycin but abrogated by cyclosporine A, azathioprine, and high doses of FK506. Low doses of rapamycin and of FK506 did not interfere with generation of regulatory cells.

Interleukin-10 but not transforming growth factor-beta is essential for generation and suppressor function of regulatory cells induced by intratracheal delivery of alloantigen.

BACKGROUND: We previously reported that intratracheal delivery of alloantigen-induced regulatory cells in mouse heart-transplantation model. Here, we investigated roles of interleukin (IL)-10 and transforming growth factor (TGF)-beta in induction and effector phases of the regulatory cells. METHODS: CBA mice were pretreated with intratracheal delivery of C57BL/10 splenocytes and administration of neutralizing anti-IL-10 or anti-TGF-beta monoclonal antibody (mAb). Seven days after the pretreatment, naive CBA mice (secondary recipients) were given adoptive transfer of splenocytes from the pretreated mice and underwent heart grafting from C57BL/10 mice. To determine roles of these cytokines in the effector phase of the regulatory cells, anti-IL-10 or anti-TGF-beta mAb was administered weekly into the secondary recipients after the adoptive transfer. RESULTS: Adoptive transfer of splenocytes from CBA mice that had been pretreated with intratracheal delivery of C57BL/10 splenocytes significantly prolonged the survival of C57BL/10 allograft (median survival time [MST] 68 days) as compared with adoptive transfer from untreated CBA mice (MST 12 days). In the induction phase, anti-IL-10 mAb abrogated development of the regulatory cells that afforded prolonged allograft survival in the secondary recipients (MST 20 days), whereas anti-TGF-beta mAb did not abrogate it (MST 88 days). In the effector phase, anti-IL-10 mAb abrogated prolonged allograft survival afforded by adoptive transfer of the regulatory cells in the secondary recipients (MST 27 days), whereas anti-TGF-beta mAb did not abrogate suppressor function of the regulatory cells (MST 53 days). CONCLUSION: IL-10 but not TGF-beta was required for generation and suppressor function of the regulatory cells induced by intratracheal delivery of alloantigen.

Surgical and endovascular procedures for treating isolated iliac artery aneurysms: ten-year experience.

Characteristics of atherosclerotic isolated iliac artery aneurysms (IAAs) and various strategies for their treatment were assessed retrospectively. The computerized medical records of 18 patients who underwent surgical or endovascular treatment of an IAA during the 10 years from April 1993 to March 2003 at our university hospital were reviewed to obtain information on patient demographics, risk factors, type of IAA treatment, and outcome. Additional data were obtained by mail and telephone. Patients with an IAA were compared with 168 patients treated for an abdominal aortic aneurysm (AAA) also at our institution. Early in the series of isolated IAA repairs, patients underwent prosthetic graft interposition ( n = 7) or thromboexclusion ( n = 4). Subsequently, patients had either endovascular thromboembolization ( n = 4) or endovascular thromboembolization with femorofemoral crossover bypass ( n = 3). No perioperative deaths occurred in the series. Deep venous thrombosis developed postoperatively in one patient; there were no other serious complications. The cumulative patency rate for the implanted interposition grafts during the mean observation time of 5.5 years was 100%. No endoleakage was observed after the endovascular procedures. In the long-term, five patients died of causes unrelated to the IAA treatment. A statistical analysis revealed no significant differences between the IAA group and the AAA group with respect to atherosclerotic risk factors. In conclusion, open surgical procedures to repair isolated IAAs generally have a good outcome, although the risk of injury to adjacent iliac veins remains. Endovascular treatments appear to have some advantages, but studies including long-term follow-up are needed to assess the efficacy and durability of prosthetic grafts used for these procedures.

Job Redesign Needs for Aged Workers.

The aim of this paper is to explore and present a proposal for redesigning elements of the workplace for agech workers. The method of research was to observe, record, and measure the actions of sitting workers performing assembly operations on electrical products in the Kani Plant Nagoya Works of Mitsubishi Electric Co. (Japan). The evaluation index used in the experiment was obtained by measuring time motion elements, cycle time per product, and motion velocity waves of elderly workers. Those motion characteristics were then compared to the motion characteristics of young workers. The results led to job redesign elements being identified to reduce handling factors of high difficulty for aged workers and to the necessity to consider a coefficient of correction in Method Time Measurement (MTM) according to differences in the manufactured object's weight.