Riverside Transplantation Institute

Hemangioma, a most frequently encountered primary benign tumor of the liver, is generally determined incidentally during the course of radiologic tests for other reasons. Most lesions are less than 3 cm and a significant proportion of patients are asymptomatic, although the size and location of the lesion in some patients may be associated with the onset of symptoms. Pressure on the stomach and duodenum of giant hemagiomas developing in the left lobe of the liver, in particular, may result in the development of abdominal pain, nausea, vomiting, and feeling bloated, which are characteristic of a gastric outlet obstruction. A 42-year-old man presented with findings of gastric outlet obstruction and weight loss as a result of a giant hepatic hemangioma.

Minimization of immunosuppression and donor-specific tolerance to MHC-mismatched organ grafts are important clinical goals. The therapeutic potential of regulatory T cells (Tregs) has been demonstrated, but conditions for optimizing their in vivo function posttransplant in nonlymphocyte-depleted hosts remain undefined. In this study, we address mechanisms through which inhibition of the mammalian target of rapamycin (Rapa) synergizes with alloantigen-specific Treg (AAsTreg) to permit long-term, donor-specific heart graft survival in immunocompetent hosts. Crucially, immature allogeneic dendritic cells allowed AAsTreg selection in vitro, with minimal expansion of unwanted (Th17) cells. The rendered Treg potently inhibited T cell proliferation in an Ag-specific manner. However, these AAsTreg remained unable to control T cells stimulated by allogeneic mature dendritic cells, a phenomenon dependent on the release of proinflammatory cytokines. In vivo, Rapa administration reduced danger-associated IL-6 production, T cell proliferation, and graft infiltration. Based on these observations, AAsTreg were administered posttransplant (day 7) in combination with a short course of Rapa and rendered >80% long-term (>150 d) graft survival, a result superior to that achieved with polyclonal Treg. Moreover, graft protection was alloantigen-specific. Significantly, long-term graft survival was associated with alloreactive T cell anergy. These findings delineate combination of transient mammalian target of Rapa inhibition with appropriate AAsTreg selection as an effective approach to promote long-term organ graft survival.

Baron, P W.1; Ben-Youssef, R1; Franco, E1; Weissman, J1; Baqai, W2; Kore, A1; DeLeon, M2; Cordero-MacIntyre, Z2; Ojogho, O1 Author Information

Mycophenolate mofetil (MMF) is a new immunosuppressive agent that blocks de novo purine synthesis in T and B lymphocytes via a potent selective inhibition of inosine monophosphate dehydrogenase. MMF has been shown to significantly reduce the incidence of acute rejection in both adult and pediatric renal transplantation. The impact of MMF on routine antibody induction therapy in pediatric renal transplantation has not been defined. Remarkably, a recent North American Pediatric Transplant Cooperative Study concluded that T-cell antibody induction therapy was deleterious for patients who received MMF. Our study examines the use of MMF in an evolving immunosuppressive strategy to avoid antibody induction in both living (LD) and cadaver (CAD) donor pediatric renal transplantation. We retrospectively analyzed the records of 43 pediatric renal transplants that received MMF-based triple therapy without antibody induction therapy between November 1996 and April 2000. We compared CAD (n = 17) with LD (n = 26). The two groups were similar demographically except that CAD had significantly younger donors than LD, 26.1 +/- 13.7 vs. 36.2 +/- 9.2 yr (p = 0.006). All the patients received MMF at 600 mg/m2/b.i.d. (maximum dose of 2 g/d) and prednisone with cyclosporine (86%) or tacrolimus (14%). Mean follow-up was >36 months for each group. Acute rejection rate at 6 months was 11.8% (CAD) vs. 15.4% (LD) (p = 0.999) and at 1 yr was 23.5% (CAD) vs. 26.9% (LD) (p = 0.999). Mean estimated glomerular filtration rate (ml/min/1.73 m2) at 6 months was 73.3 +/- 15.3 (CAD) vs. 87.6 +/- 24.2 (LD) (p = 0.068). Patient survival at 1, 2, and 3 yr was 100, 100, and 100% for CAD vs. 100, 96, and 96% for LD, respectively. Graft survival at 1, 2, and 3 yr was 100, 100, and 94% for CAD vs. 96, 88, and 71% for LD, respectively. Graft loss in CAD was because of chronic rejection (n = 2) while in LD it was because of non-compliance (n = 6), post-transplant lymphoproliferative disorder (n = 1), and sepsis (n = 1). In conclusion, MMF without antibody induction in both CAD and LD pediatric renal transplantation provides statistically similar and effective prophylaxis against acute rejection at 6 months and 1 yr post-transplant. The short-term patient and graft survival rates are excellent, however, non-compliance remains a serious challenge to long-term graft survival. Additional controlled studies are needed to define the role of MMF without antibody induction therapy in pediatric renal transplantation.

Recombinant adenovirus (rAd) infection is one of the most effective and frequently employed methods to transduce dendritic cells (DC). Contradictory results have been reported recently concerning the influence of rAd on the differentiation and activation of DC. In this report, we show that, as a result of rAd infection, mouse bone marrow-derived immature DC upregulate expression of major histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma interferon, and tumor necrosis factor alpha mRNAs, without effects on other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35. These effects were not related to specific transgenic sequences or to rAd genome transcription. The rAd effect correlated with a rapid increase (1 h) in the NF-kappaB-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-IkappaB, an rAd-encoding the dominant-negative form of IkappaB. In vivo studies showed that after intravenous administration, rAds were rapidly entrapped in the spleen by marginal zone DC that mobilized to T-cell areas, a phenomenon suggesting that rAd also induced DC differentiation in vivo. These findings may explain the immunogenicity of rAd and the difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.

Erythropoietic protoporphyria (EPP) is marked by a deficiency of ferrochelatase, which occurs in all cells and tissues, preventing effective conversion of proto porphyrin IX to heme and thereby blocking effective feedback inhibition of heme synthesis. The major source of the excess protoporphyrin is the bone marrow. Protoporphyrin IX may accumulate, with resultant toxicity chiefly of the marrow, skin, nervous system, and liver. Orthotopic liver transplantation (OLT) is, at present, the only adequate intervention for severe liver compromise secondary to protoporphyrin deposition, but it has been complicated by severe photosensitivity and polyneuropathy. Intravenous heme and plasmapheresis have been proposed but not previously reported as means to reduce the protoporphyrin burden before liver transplantation. We report a man with EPP who underwent preoperative heme-albumin administration and plasmaphereses that led to marked reductions in plasma and erythrocyte protoporphyrin levels. His OLT was uneventful, and he developed neither polyneuropathy nor exacerbation of photosensitivity.

トーマススターツル移植施設における, 免疫抑制剤タクロリムスを使用した1990年から1998年までの小児小腸移植64例68回の患者とグラフト生存, 拒絶反応などの成績について報告する.小腸不全の内訳は腸捻転 (n= 18), 腹壁破裂 (n= 16), 腸閉鎖 (n= 8), 壊死性腸炎 (n= 7), 腸管偽閉塞症 (n= 6), ヒルシュプルング病 (n=4), microvillous inclusion disease (n= 3), ポリポーシス (n= 1) および外傷 (n= 1) であった.移植手術は, 小腸単独移植 (n= 19), 肝小腸複合 (n= 39) および多臓器移植 (n= 10) であった.現在まで33グラフトが生存しており, 5年の患者とグラフト生存は59%および53%であった.年齢別のグラフト5年生存率は2歳未満43%で, 10歳以上が89%と最も良好であった.小腸単独, 肝小腸複合と多臓器移植の5年グラフト生存は67%, 46%と35%であった.小腸の急性拒絶反応は100%, 肝臓のそれは38%にみられ, 一か月以内の拒絶反応は小腸80%, 肝臓14%であった.ステロイド抵抗性の拒絶反応によるOKT3の投与は小腸単独に多かった.グラフト摘出は10例で.原因は拒絶7例, 膵炎, PTLD (posttransplant lymphoproliferative disease) と肝動脈血栓症が各々1例であった.再移植は計5例で, 3例は拒絶や敗血症, PTLDで死亡した.Graftversus-host disease (GVHD) は10例に発生し, この内3例は拒絶によるグラフト摘出後に見られた.Exfoliative拒絶は12例, 14グラフトにみられ, 8人が死亡し, 10グラフトが喪失した.グラフト喪失は36例 (52%) にみられ, 原因は急性拒絶9例, PTLD9例, 手術手技的合併症6例, 感染と敗血症7例, 拒絶とPTLD3例, 膵炎と不明が各1例であった.現在, 33例中31例 (94%) のグラフトが経口摂取のみで生存している.小腸移植は腎, 肝, 心移植と較べ, 手術合併症や高頻度, 高度の拒絶反応により, 患者やグラフト生存も不良であるが, 現状では, TPN合併症を有する不可逆性小腸不全症の唯一の治療法である.しかし, 拒絶反応に対する過剰な免疫抑制はEBV感染症を招きPTLDの誘因となり, 逆に過小な免疫抑制で拒絶やrebound拒絶を引き起こす, 非常に安全域の狭い実験段階の治療である.