Mixed hematopoietic chimerism prevents allograft vasculopathy.

BACKGROUND: Mixed hematopoietic chimerism has been shown to induce long-term acceptance of transplant organs. We determined whether mixed chimerism prevented allograft vasculopathy, using the rat aortic allograft model. METHODS: Mixed chimeras were prepared by reconstituting lethally irradiated (1100 cGy) WF rats with a mixture of T-cell depleted (TCD) syngeneic (WF) plus TCD allogeneic (ACI) bone marrow. Donor-specific (ACI) or third-party (F344) aortic grafts were transplanted into mixed chimeric animals 1 to 2 months after bone marrow reconstitution. No immunosuppressive drugs were administered. At 30 days postoperatively, aortic allografts were harvested for histology and measurement of cytokine mRNA by semiquantitative RT-PCR. Some aortic grafts were harvested at 90 and 180 days after transplantation for histological analysis. The degree of intimal hyperplasia and cytokine gene expression were compared among 4 groups: I (syngeneic; ACI donors to ACI recipients), II (allografts; ACI to WF), III (donor specific; ACI donor to chimeras) and IV (third-party; F344 to chimeras). RESULTS: There was no difference in the degree of intimal hyperplasia (IH) between groups I and III. Groups II and IV had significantly more IH than group I. Compared to group I, levels of mRNA for IFN-y, IL-2, IL-10 and iNOS in groups II and IV were higher, while there was no difference in mRNA levels between group I and III. CONCLUSIONS: These data suggest that mixed chimerism prevents allograft vasculopathy. Mixed chimerism holds great promise in clinical transplantation as a means to prevent allograft vasculopathy.     

Ingested interferon-alpha prevents allograft islet transplant rejection

BACKGROUND: Ingested interferon (IFN)-alpha is a biological response modifier in experimental autoimmune encephalomyelitis and multiple sclerosis, and prevents type 1 diabetes in nonobese diabetic mice. Islet transplantation possesses significant potential advantages over whole-gland transplantation because it is simple, may achieve insulin independence, and has clear advantages over exogenous insulin therapy. Therefore, we examined whether ingested IFN-alpha, administered to islet allograft recipients, could prevent islet allograft rejection. METHODS: Recipient C3H mice (H2k) were made diabetic and either untreated or treated with 10-1000 international units (IU) of ingested murine IFN-alpha daily from day -7 through day +14 after transplantation for a total of 21 days. Seven days after diabetes induction, recipients received allograft islets isolated from C57BL.10 donors (H2b) under the kidney capsule and were followed for overt diabetes via elevated blood glucose. RESULTS: Control recipients and recipients fed 1000 IU all became diabetic by day 13, whereas mice ingesting IFN-alpha had delayed rejection for up to 27 (10 IU) to 29 days (100 IU) after islet transplantation. Treatment of recipients of islet allografts with ingested IFN-alpha doubles the time period before rejection compared with control mice. The feeding period with daily IFN-alpha was doubled from 21 days to 42 days in total, 7 days before transplantation and 35 days after transplantation. CONCLUSION: Treatment of recipients of islet allografts with prolonged ingested IFN-alpha prevents rejection in a subset of recipients. Ingested IFN-alpha may prevent rejection if given continuously after transplantation.     

Desferrioxamine treatment prevents chronic islet allograft damage

BALB/cByJ islet allografts are acutely rejected when transplanted into allogeneic mice (CBA/J). Culture of the tissue for 7 days in 95% O2 before grafting is a suboptimal treatment for the reduction of immunogenicity in this strain combination. Approximately half the animals reject these transplants in a chronic fashion. Chronic islet rejection differs from acute rejection of uncultured allogeneic islets. During chronic rejection, beta cells within the transplanted tissue degranulate but remain intact when the animal returns to the diabetic condition. Acute islet rejection is characterized by the destruction of beta cells that remain heavily granulated as long as they remain intact. We examined the effect of the iron chelating agent, desferrioxamine, on chronic islet allograft damage. Desferrioxamine inhibited chronic islet allograft damage but did not influence the process of rejection of uncultured islet tissue. This effect of desferrioxamine could not be attributed to a direct immunosuppressive effect of this agent.     

Recipient hypertonic saline infusion prevents cardiac allograft dysfunction

Objective

Hypertonic saline (HTS) has potent immune and vascular effects. We assessed recipient pretreatment with HTS on allograft function in a porcine model of heart transplantation and hypothesized that HTS infusion would limit endothelial and left ventricular (LV) dysfunction following transplantation.

动脉液压扩张在组织移植中的应用

目的观察组织移植过程中动脉在应用节段性液压扩张后不同时间的通畅率和动脉痉挛发生率,并通过组织学研究观察液压扩张对动脉结构的影响。方法对57例拇、手指缺失的患者,应用?甲瓣游离移植拇指再造41例,应用第二足趾游离移植拇指再造6例,应用第二、三足趾游离移植手指再造10例。组织完全游离后,用300mmHg的压力对足背动脉注入肝素 生理盐水进行节段性液压扩张,扩张后再行血管吻合。足背动脉液压扩张后(压力为300mmHg)做组织学检查,观察动脉内皮细胞、内弹力膜与平滑肌的变化。结果1移植组织在术后24～120h皮温平均高于健指0.16℃。2术后血管即刻通畅率为100%,动脉痉挛发生率为0。24h后,有1例因血肿压迫而出现危象,压迫解除后,血循环恢复。1例因毛细血管床广泛血栓形成导致失败,手术成功率为98.2%。3病理改变经液压扩张的动脉内皮细胞有15%脱落,内弹力膜轻度松弛,肌层基本正常,厚薄不一;未经液压扩张的动脉内皮细胞有7%脱落,内弹力膜厚薄一致,肌层完整。结论1节段性液压扩张是防止及治疗痉挛的有效方法之一,只要掌握适当压力,血管扩张充分,对于减少动脉血管的痉挛,提高组织移植成功率是安全、有效的。2一定压力(300mmHg)的液压扩张对动脉壁结构无明显影响。     

A proteasome inhibitor effectively prevents mouse heart allograft rejection

BACKGROUND: We have previously demonstrated in vitro that proteasome inhibitors could suppress proliferation and induce apoptosis of activated T cells. This finding suggests that such inhibitors could be used as a novel category of immunosuppressants in blocking allograft rejection. METHODS: The proteasome inhibitor dipeptide boronic acid (DPBA) was tested in vitro for its inhibitory effect on mouse T-cell proliferation and lymphokine secretion. DPBA was also used in vivo to treat mouse heterotopic heart allograft rejection. Possible side effects of this compound were examined according to blood chemistry of mice treated with DPBA. RESULTS: DPBA suppressed the T-cell proliferation and potently inhibited interleukin (IL)-2, IL-6, IL-10, IL-13, and IFN-gamma produced by anti-CD3-activated T cells. Given i.p. starting 1 day after transplantation at 0.66 mg/kg per day for 16 days, or at 1 mg/kg per day for 4 days followed by 0.5 mg/kg per day for 12 days, DPBA could prolong heart allograft survival to 35.5 days (mean survival time, MST) and to 36.2 days, respectively. The control group had MST of 7.3 days. When administrated 72 hr post operation at 1 mg/kg per day for 4 days, DPBA could prolong the graft survival to 19.8 days. During the course of these effective dosages, DPBA had no apparent toxicity in the liver, kidney, pancreas, or heart, according to analysis of blood chemistry. CONCLUSIONS: The proteasome inhibitor could repress allograft rejection in mice without apparent side-effects at the effective dosages. This finding has opened a new dimension in development of novel immunosuppressants for organ transplantation.     

Gastroduodenal arterial reconstruction of the pancreaticoduodenal allograft

Simultaneous procurement of the pancreas and liver necessitates division of vessels supplying both organs. The integrity of the pancreatic arterial supply appears to be related to surgical complications after pancreas transplantation. We have described herein three cases of gastroduodenal artery (GDA) reconstruction during pancreas transplantation, and reviewed other options for GDA reconstruction. These techniques performed safely during bench reconstruction can be applied to various clinical situations.     

尸体动脉建立动静脉内瘘术

目的 动静脉内瘘是慢性肾功能衰竭血液透析患者的重要“生命线”,但一些长期透析患者,由于多次手术及反复穿刺,上肢前臂已无可供做内瘘吻合的动静脉。我们采用尸体动脉作为移植血管制作动静脉内瘘。方法 将尸体动脉用乙醚及无水乙醇处理,保存于75％乙醇内。将尸体动脉作为移植血管制作动静脉内瘘3例。结果 术后血流通畅,血流量200-275ml·min-1。结论 用尸体动脉作为移植血管制作动静脉内瘘效果满意。     

Early rupture of a cryopreserved arterial allograft

Cryopreserved arterial allografts are used in vascular surgery to treat infected arterial prosthesis. This treatment reduces mortality and morbidity compared to conventional surgery. We observed a case of early rupture of the allograft with the death of the patient due to a misdiagnosis. Recent findings show that cases of rupture have been described, and that current cryopreservation protocols may be the cause of degeneration. To avoid a sudden death for the patient, this complication must be known to diagnose quickly and treat surgically before a final haemorrhagic shock.     

Hepatocyte growth factor prevents chronic allograft dysfunction in liver-transplanted rats

BACKGROUND: Hepatocyte growth factor (HGF) is a growth factor with multiple biologic properties, including mitogenic, morphogenic, anti-apoptotic, and antifibrogenic activities. Long-term administration of the deletion variant of HGF (dHGF) might contribute to the prevention of chronic liver allograft dysfunction, which is attributed to immunologic and nonimmunologic reactions. METHODS: Low-dose tacrolimus was administered to rat-liver recipients after transplantation. Effects of dHGF on transplanted livers treated with low-dose tacrolimus were investigated. RESULTS: Rats receiving liver transplants treated with only low-dose tacrolimus administration showed chronic allograft dysfunction. Treatment with dHGF prolonged the survival time of rats that received liver allografts and suppressed fibrosis of liver allograft. Treatment with dHGF also suppressed the expression levels of interleukin (IL)-1beta, caspase-1, and transforming growth factor (TGF)-beta mRNAs in liver allografts. CONCLUSIONS: The findings indicate that dHGF may prevent chronic liver-allograft dysfunction and thus may become a novel treatment for chronic liver-allograft dysfunction.     

In vitro allograft irradiation prevents graft-versus-host disease in small-bowel transplantation

In small-bowel transplantation, the transfer of large numbers of donor lymphocytes with the intestinal allograft may provoke a lethal graft-versus-host reaction. The effectiveness of allograft irradiation in vitro as a method of preventing graft-versus-host disease (GVHD) was studied in a rat model of small-bowel transplantation, with the Lewis----Lewis X Brown Norway F1 hybrid strain combination. Cold harvested small-bowel allografts were irradiated immediately prior to heterotopic or orthotopic transplantation. Animals that had received heterotopic allografts irradiated with 0, 250, or 500 rad all died of GVHD after 14.4 +/- 3.0, 15.0 +/- 1.3, and 14.2 +/- 1.9 days, respectively. None of the animals that had received allografts treated with 1000 rad developed clinical or pathologic evidence of GVHD, however, and all survived for more than 6 months (P less than 0.001). Allograft function was studied in animals that underwent orthotopic transplantation. Recipients of nonirradiated orthotopic allografts all died of GVHD after 14.0 +/- 0.7 days, whereas recipients of allografts irradiated with 1000 rad all survived for more than 5 months (P less than 0.001). After 120 days, weight gain (51.8 +/- 11.7%), serum albumin (3.9 +/- 0.7 g/dl), serum triglycerides (67.0 +/- 24.3 mg/dl), CBC, and differential in these animals were not statistically different from those in either age-matched isograft recipients or normal animals, and when the rats were sacrificed, irradiated allografts showed no changes suggestive of radiation injury. These results indicate that irradiation of small-bowel allografts in vitro prevents development of GVHD, and that this can be achieved at a dose which does not cause injury to or malfunction of the allograft.     

Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy

Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common gamma chain. The rationally designed inhibitor of JAK3, CP-690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP-690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1(a)) or Lewis (RT1(l)) rats were heterotopically transplanted into the infra-renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP-690,550 by osmotic pumps (mean drug exposure of 110 +/- 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 +/- 0.85% vs. 0.43 +/- 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 +/- 2.4% vs. 0.38 +/- 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP-690,550-treated animals also had a significant reduction of donor-specific IgG production and of the gene expression for suppressor of cytokine signaling-3 and with unchanged levels of expression of RANTES, IP-10 and transforming growth factor-beta1. These results are the first to show that JAK3 blockade by CP-690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.     

Aortic graft infections: treatment with arterial allograft

Since its reintroduction by Kieffer in 1991, many authors have used arterial allografts for surgical management of vascular prosthetic graft infection. During a decade, 25 patients with aortic graft infection were treated using in situ revascularization with arterial allograft. There were 23 male and 2 female patients of mean age of 65.7 +/- 8.8 years (range, 43-78). Antibiotic therapy was administered for a mean time of 26 +/- 5 days (range, 21-45) in the postoperative period. The mean follow-up time was 2.3 +/- 3 years (range, 22 days-8.7 years). The mean in-hospital postoperative stay was 29.6 +/- 14 days (range, 9-68). An aorto-enteric fistula (AEF) was present in 11 patients (44%), producing gastrointestinal bleeding. The overall mortality rate was 13 of 23 (56.5%) patients. The allograft-related mortality rate was 5 of 23 (22%). The overall allograft-complicated patient rate was 15 of 23 (65%); we observed 18 allograft ruptures in 12 patients and 8 allograft thromboses in 6 patients. The overall amputation rate was 8.7% (2 of 23). Age of the recipient older than 69 years (P = .02), positive preoperative marked-leukocyte scanning (P = .04), and persistent postoperative leukocytosis (P = .03) were significant variables associated with an increased risk of allograft-related complications. The use of arterial allografts for aortic graft infections represents an interesting alternative for the treatment of graft infection. Nevertheless, there are some problems related to the durability of this type of graft, which can still be considered as a "bridge transplant."     

Cryopreserved arterial allograft reconstruction for peripheral graft infection

OBJECTIVE: This prospective, observational study evaluated the safety and efficacy of cryopreserved arterial allograft reconstruction in the management of major peripheral arterial graft infections. METHODS: From April 1996 to May 2003, data from patients with major peripheral arterial graft infection who underwent graft excision and cryopreserved arterial allograft reconstruction were prospectively collected. Arterial allografts were harvested from multiple organ donors and cryopreserved at -80 degrees C. The patients were observed for survival, limb salvage, persistence or recurrence of infection, and allograft patency. The results were calculated with the Kaplan-Meier method. RESULTS: During the 7-year study period, 17 patients (14 men, 3 women; mean age, 68 years) with major peripheral graft infection underwent graft excision and cryopreserved arterial allograft reconstruction. Eight patients (47%) had systemic sepsis, 5 (29%) had acute ischemia at the time of the allograft reconstruction, and 9 (53%) had experienced anastomotic rupture. Allograft reconstruction was performed as an emergency procedure in 7 patients (41%). There were no perioperative deaths or early amputations. Two patients had allograft ruptures in the groin during the early postoperative period. The mean follow-up period was 34 months (range, 8 to 80 months). There was no persistent or recurrent infection, and none of the patients received long-term (>3 months) antibiotic therapy. Reoperation for allograft revision, excision, or replacement was performed in 2 patients. The 18-month primary and secondary allograft patency rates were 68% and 86%; the overall limb salvage rate was 82% at 2 years. CONCLUSION: Our experience with cryopreserved arterial allograft in the management of major peripheral bypass graft infection suggests that this technique seems to be a useful option for treating one of the most dreaded vascular complications.