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Biomedical subjects

K Dono

Publications and source records attributed to K Dono.

At least 55 records · Page 3Linked to original sources
PubMed1998

Direct antigen presentation through binding of donor intercellular adhesion molecule-1 to recipient lymphocyte function-associated antigen-1 molecules in xenograft rejection.

Cellular interactions that lead to graft rejection were examined in a rat-to-mouse xenogeneic combination using species-specific monoclonal antibodies (mAbs) against donor and recipient intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) molecules, respectively. Although both mAbs displayed moderate blocking activity in an in vitro mixed lymphocyte response assay, strong suppression was observed when anti-donor (rat) ICAM-1 mAb was combined with anti-recipient (mouse) LFA-1 mAb. Likewise, significant prolongation of islet xenograft survival was observed with these mAbs. Thus, 0.05 mg of anti-mouse LFA-1 mAb and anti-rat ICAM-1 mAb given on days 0 and 1 produced significant prolongation of graft survival over the control (51+/-20 days vs. 10+/-3 days, P<0.0001), but not when anti-mouse ICAM-1 mAb was combined with anti-mouse LFA-1 mAb (13+/-3 days). In this species combination, mouse T cells were able to proliferate in the presence of rat antigen-presenting cells (APCs) in a cell number-dependent manner, but not in the presence of mouse APCs. The binding assay showed that LFA-1 molecules on mouse T cells can bind immobilized rat ICAM-1 molecules. These results suggest that rat ICAM-1 molecules on APCs can interact with mouse LFA-1 molecules on T cells across a species barrier and that this binding generates the consequent immune responses leading to rejection. mAb treatment against these adhesion molecules of recipient as well as donor is crucial for preventing rejection in a xenogeneic transplantation model.

Animals↗
PubMed1998

Protection of islet allografts transplanted together with Fas ligand expressing testicular allografts.

Fas ligand (FasL) is highly expressed in testicular tissues and thought to be responsible for protection from allograft rejection by inducing apoptosis of anti-graft activated T cells. FasL-expressing islets have been shown to induce a granulocyte-mediated inflammatory reaction. We investigated whether a graft can be protected from alloimmune responses by manipulating the Fas/FasL-system. We transplanted allogeneic islets under the kidney capsule of streptozotocin-induced diabetic mice together with testicular tissue. Significant prolongation of survival of C3H islet allograft was observed in C57BL/6 (B6) recipients transplanted with C3H testicular tissue, but not in those transplanted with C3H-gld testicular tissue expressing non-functional FasL. No significant prolongation was observed in B6-lpr recipients expressing non-functional Fas. Immunohistochemical staining of C3H testicular tissue in the composite graft showed a high expression of FasL, but not that of the C3H-gld testicular tissue. In situ terminal deoxynucleotidyl transferase-mediated dUDP-biotin catalysed DNA nick-end labelling (TUNEL) staining of a composite graft of C3H islet and testicular tissue in B6 recipients demonstrated extensive apoptosis of infiltrating mononuclear cells around the graft. The protective effect of C3H testicular tissue was abrogated when anti-FasL monoclonal antibody was administered i.p. postoperatively. Our results suggest that FasL-positive testicular allografts protect composite islet allografts and indicate that manipulation of Fas/FasL mediated apoptosis is a suitable strategy for controlling rejection of islet allografts.

Animals↗
PubMed1997

Awareness of donor alloantigens in antiadhesion therapy induces antigen-specific unresponsiveness to islet allografts.

BACKGROUND: Antiadhesion therapy using monoclonal antibodies (mAbs) to adhesion molecules in vivo has been shown to produce significant prolongation of graft survival in various transplantation models. However, it remains unclear whether antiadhesion therapy operates by merely blocking adhesion between antigen-presenting cells and T cells physically and/or by blocking costimulatory signals while preserving signals mediated through T-cell receptors in vivo. We examined antigen-specific T-cell responses during and after antiadhesion therapy. METHODS: BALB/c islets were transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 mice given anti-lymphocyte function-associated antigen (LFA)-1 and/or anti-intercellular adhesion molecule-1 mAb treatment. The animals bearing surviving islet allografts were challenged with BALB/c or third-party islets on day 7 or more than 100 days after transplantation. RESULTS: Islet allografts were acutely rejected in untreated animals, with a mean survival time (MST) of 19+/-8 days. Administration of anti-LFA-1 mAb induced significant prolongation of graft survival with a mean survival time of 72+/-33 days, and half of the allografts showed indefinite survival. The animals given anti-LFA-1 mAb alone 7 days before transplantation showed acute rejection of BALB/c islets, whereas a significant number of animals given anti-LFA-1 mAb and the BALB/c islet allograft simultaneously accepted secondary BALB/c islets, but rejected third-party islets. Likewise, most of the animals bearing long-term functioning BALB/c allografts for more than 100 days accepted secondary BALB/c islets, but rejected C3H islets acutely. Interestingly, the spleen cells from these animals transferred unresponsiveness to BALB/c islets into the 2.5-Gy x-irradiated recipients, whereas those from naive animals induced acute rejection. CONCLUSIONS: These results indicate that anti-LFA-1 mAb treatment prevents T-cell activation leading to rejection, but results in a T-cell receptor engagement leading to antigen-specific unresponsiveness maintained by transferrable suppressor cells.

Animals↗
PubMed1997

[Transarterial immuno-embolization therapy in patients with hepatocellular carcinoma].

Surgical resection, transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) are effective for hepatocellular carcinoma (HCC), but the recurrence rate is high. We have devised a new therapy of transarterial immuno-embolization (TIE) with OK-432, fibrinogen and thrombin, and 2 cases are reported. Case 1: A 78-year-old Japanese male with HCC (diameter, 4 cm in subsegment 5) received TIE. The tumor size was markedly decreased, and the patient survived for more than 3 years without recurrence. Case 2: A 61-year-old Japanese male with HCC (diameter, 4.5 cm in segment 5) received hepatic subsegmentectomy following TIE. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells in the main tumor. Tumor recurrence had developed three times thereafter, but was effectively treated by TIE. TIE may be an effective therapy for HCC.

Aged↗
PubMed1996

[Locoregional injection of OK-432/fibrinogen/thrombin for unresectable metastatic liver tumors].

We performed the locoregional injection of OK-432/fibrinogen/thrombin to unresectable hepatic tumors metastasized from colorectal cancers, which were hardly controlled by arterial infusion chemotherapy. CEA was markedly decreased following this treatment, although abdominal CT did not show a significant reduction of tumor mass. This immuno-injection therapy may be a choice of treatment for metastatic liver tumors, refractory to treatment by conventional chemotherapy.

Antineoplastic Agents↗
PubMed1995

Induction of tolerance to skin allografts by intrathymic injection of donor splenocytes. Effect of donor-recipient strain combination and supplemental rapamycin.

The effect of donor-recipient strain combination and supplemental rapamycin (Rapa) on tolerance induction by intrathymic (IT) injection of donor splenocytes was examined in a mouse skin allograft model. In an MHC class I-mismatched C3H/He skin to (C57BL/6 x A)F1 (B6AF1) mouse combination, IT injection of 50 x 10(6) donor splenocytes with transient immunosuppression by rabbit anti-mouse lymphocyte serum (ALS) induced significant prolongation of skin allograft survival with a median survival time (MST) of 115 days versus an MST of 24.5 days in controls given ALS alone. With an additional short course of supplemental Rapa treatment at a dose of 1.5 mg/kg i.p. every other day from day 0 to 12, all C3H/He skin allografts survived indefinitely (> 350 days) in ALS-treated, donor splenocyte intrathymically injected B6AF1 recipient mice. Tolerance was antigen-specific, since the second donor-type skin allografts were accepted while third-party skin allografts were acutely rejected in these mice bearing long-term C3H/He skin allografts. In MHC class I- and II-disparate (DBA/2 to B6AF1) and fully MHC-incompatible (AKR to B6) strain combinations, IT injection of donor splenocytes and ALS treatment failed to prolong skin allograft survival over ALS controls. When supplemental Rapa was used, long-term skin allograft acceptance was observed with an MST of 127 days for the DBA/2 to B6AF1 combination and 70 days for the AKR to B6 combination. In contrast, supplemental treatment with cyclosporine was not effective in these combinations, which suggests that supplemental Rapa may have a unique effect in augmenting IT tolerance induction. Thymectomy within 7 days after IT injection significantly shortened the allograft survival, which suggests that interaction of the host thymus and the injected donor splenocytes, which takes place early after IT injection, plays an important role in the induction of allograft tolerance in this model.

Animals↗
PubMed1995

Marked prolongation of rat skin xenografts induced by intrathymic injection of xenogeneic splenocytes and a short course of rapamycin in antilymphocyte serum-treated mice.

The effect of intrathymic (IT) injection of donor splenocytes and a short course of rapamycin (Rapa) treatment on rat to mouse skin xenograft survival was investigated. ACI rat skin xenografts were transplanted to (C57BL/6 x A)F1 mice treated with rabbit anti-mouse lymphocyte serum (ALS) on days -1, +2, and +4 relative to skin grafting on day 0. Fifty million donor-type splenocytes were injected intrathymically on day 7 after transplantation. Rapa was given intraperitoneally every other day from day 0 to day 12 at a dose of 3.0 mg/kg. Prolonged skin xenograft survival was observed in ALS- and Rapa-treated recipients (no IT injection) with a median survival time of 47 days. However, skin graft survival was markedly more prolonged in the group treated with ALS, Rapa, and IT injection of donor splenocytes did not have a beneficial effect on skin xenograft survival in ALS-treated recipients. An increased presence of donor-type cells was observed in the thymus of the ALS- and Rapa-treated recipients for 7 days after IT injection of donor splenocytes. In conclusion, a short course of Rapa markedly augments rat skin xenograft survival in ALS-treated mice injected intrathymically with donor-type splenocytes.

Animals↗
PubMed1995

A protocol with FK 506 for inducing unresponsiveness to murine islet allografts.

BACKGROUND: The most favorable protocol for transplantation is inducing unresponsiveness before operation by means of nondangerous modalities. This would permit discontinuance of long-term use of immunosuppressants. In this study we developed a potential protocol for inducing unresponsiveness to islet allografts by preoperative donor spleen cell inoculation (DSI) and a single injection of FK 506. METHODS: BALB/c (H-2d) and C57BL/6 (H-2b) mice were used as islet donors and recipients, respectively. The streptozocin-induced diabetic mice that had been given DSI at a dose of 1 x 10(7) or 1 x 10(4) and a single injection of FK 506 (10 mg/kg intramuscularly) at different schedules (on day 1, 3, 5, or 7 relative to DSI on day 0) were subjected to islet allografting on day 10. RESULTS: All islet recipients returned to normoglycemia within a few days with no toxic effect of FK 506 treatment. DSI at a dose of 1 x 10(7) alone led to shortening of the mean survival time to 10.1 +/- 4.1 days, as compared with 13.5 +/- 6.3 days for the untreated animals. In contrast, marked prolongation of graft survival was induced when FK 506 was given on day 3 (> 84 +/- 27.3 days, p < 0.0001) or on day 5 after DSI (> 50.9 +/- 46.0 days, p < 0.05). Five of seven allografts given FK 506 on day 3 and three of seven allografts given FK 506 on day 5 survived indefinitely. Other time schedules of DSI and FK 506 treatment (on day 1 or 7 after DSI) or FK 506 treatment alone had no significant effect on mean survival time. With the same protocol, third-party islet allografts (C3H) were immediately rejected (10.6 +/- 2.6 days). CONCLUSIONS: Prolongation of islet allograft survival was induced by certain doses of DSI and preoperative FK 506 treatment. This modality prevents an adverse effect of FK 506 on grafted islets and can induce unresponsiveness to islet allografts, offering a protocol for successful clinical islet transplantation.

Animals↗
PubMed1994

Low temperature collagenase digestion for islet isolation from 48-hour cold-preserved rat pancreas.

We examined the efficacy of relatively low temperature collagenase digestion at 20 degrees C on the yield and viability of islets after long-term cold preservation. Wistar rat pancreases were distended with University of Wisconsin solution via a pancreatic duct at the time of harvesting to which collagenase and 2.5 mM calcium chloride were added. The pancreases were cold-preserved at 4 degrees C for 24 or 48 hr. After storage, they were incubated for collagenase digestion at 37 degrees C or 20 degrees C for various incubation periods to obtain the peak yield. At 20 degrees C, in vitro collagenase activity measured by the FALGPA method was one fourth of that at 37 degrees C, and pancreases were well digested with a prolonged digestion period (60-90 min vs. 15-20 min for the 37 degrees C group). In vitro insulin secretion of islets isolated from freshly removed pancreases was maintained at 20 degrees C for 120 min in University of Wisconsin solution as compared with 30 min at 37 degrees C. Therefore, the preserved pancreases used in this study were incubated either at 37 degrees C or 20 degrees C at various times in order to obtain peak islet yields. The islet yields from 24-hr cold-preserved pancreases at 37 degrees C and 20 degrees C digestion were 573 +/- 59/rat (n = 6) and 497 +/- 84/rat (n = 11), respectively, and those from 48-hr cold-preserved pancreases were 395 +/- 113/rat (n = 6) and 414 +/- 75/rat (n = 6), respectively. The yields from 24- and 48-hr cold-preserved pancreases were significantly low compared with 635 +/- 52/rat for fresh pancreases (n = 15), but there was no significant difference between the 2 methods. The viability of the isolated islets, which was examined by transplantation to streptozotocin-induced diabetic C57BL/6 mice, showed a significant difference in the capacity to ameliorate diabetes. The functional success rate of islet transplantation after 24-hr cold preservation was equally good (8/8 for 37 degrees C group vs. 9/10 for 20 degrees C group), but the rate for those from 48-hr cold-preserved pancreases was significantly better with digestion at 20 degrees C than at 37 degrees C (1/8 for 37 degrees C group vs. 7/8 for 20 degrees C group, P < 0.05). We concluded that viable islets can be isolated from 48-hr cold-preserved pancreases with the low temperature collagenase digestion method, which shows promise as a modality for successful clinical islet transplantation.

Animals↗
PubMed1994

A potential immunosuppressive effect of anti-lymphocyte function-associated antigen-1 monoclonal antibody on islet transplantation.

The immunosuppressive potentials of mAbs to lymphocyte function-associated antigen-1 (LFA-1) and CD2 molecules were examined in murine islet transplantation. Crude digested islets from BALB/c (H-2d) mice were transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 (H-2b) mice. The rat mAbs of KBA (anti-LFA-1) and RM2-1 (anti-CD2) were given intraperitoneally immediately after transplantation and on the first day after grafting at a dose of 0.1 mg/mouse/day. In nontreated animals, the islet allografts were acutely rejected with a mean survival time (MST) of 19.6 +/- 8.3 days. Control isotype-matched anti-CD18 treatment did not prolong the MST of 12.8 +/- 1.6 days. Anti-LFA-1 treatment alone produced indefinite survival in 5 of 10 recipients with MST of 72.2 +/- 33.4 days. Anti-CD2 treatment failed to do so, although MST was marginally prolonged to 32.8 +/- 20.5 days. When both mAbs were given together, additional benefit with anti-CD2 treatment was not observed (MST: 77.4 +/- 31.1 days). In spite of the unresponsiveness to islet allografts, the animals did not suffer from any severe infectious disease. Mice bearing long-term functioning islets rejected third-party skin grafts as well as islet donor strain skin grafts. The long-term surviving islet allografts were also rejected coincidentally. These results indicate that a perioperative short course of anti-LFA-1 mAb treatment can induce unresponsiveness to islet allografts, although it is not systemic, and that costimulatory signals through these adhesion molecules play a central role in inducing an immune response leading to rejection of the allografted islets.

Animals↗
PubMed1992

[The efficacy of transcatheter arterial infusion chemotherapy in patients with hepatocellular carcinoma].

The efficacy of transcatheter arterial infusion chemotherapy was examined for patients with hepatocellular carcinoma (HCC) between April 1986 and May 1992. We investigated the serial serum AFP level in patients with HCC. In 9 of 18 patients, the AFP level decreased promptly to 70% of the pretreatment level after this treatment. In 29 HCC patients with intrahepatic metastasis or portal thrombosis, 10 cases survived more than one year. However, only 3 cases survived more than two years after treatment. Our results suggest that we should carefully select appropriate drugs sensitive to HCC and also give careful consideration to the resistance to anti-cancer drugs.

Administration, Oral↗