Schrepfer Sonja, Deuse Tobias, Koch-Nolte Friedrich, Krieger Thorsten, Haddad Munif, Schäfer Hansjörg, Pelletier Marc P, Robbins Robert C, Reichenspurner Hermann
University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
J Heart Lung Transplant. 2007 Jan;26(1):70-7. doi: 10.1016/j.healun.2006.10.013.
This study examines the efficacy of FK778 regimens for prevention of different phases of xenograft rejection.
Antibody and complement tissue depositions were measured by immunofluorescence in a discordant ex vivo rat-to-human heart perfusion model of hyperacute rejection with immunosuppressant-enriched human blood. The concordant hamster-to-rat aortic xenotransplantation model was used to assess host cellular (lymphocyte activation, mixed lymphocyte reaction [MLR]) and humoral responsiveness (xenoantibody production) as well as histologic xenograft rejection. Recipients were treated for 14 days with FK778, tacrolimus, sirolimus or combination regimens at varying doses.
Antibody binding during hyperacute rejection was unaffected by the immunosuppressive treatment, but complement deposition was reduced in the following order: tacrolimus > FK778 approximately sirolimus. FK778 most effectively reduced complement factor 5 in vitro. In untreated rats with hamster aortic xenografts, a large infiltrative response was observed within the grafts with extensive myocyte necrosis. Tacrolimus > FK778 approximately sirolimus dose-dependently diminished xenograft infiltration and in the same order reduced vessel-wall myocyte necrosis. Tacrolimus approximately FK778 > sirolimus reduced in vivo lymphocyte CD25 expression and tacrolimus > FK778 approximately sirolimus diminished MLR. Xenoreactive IgM and IgG antibody production levels were vigorously upregulated a few days after transplantation, but were significantly reduced by tacrolimus > FK778 approximately sirolimus. Combination regimens revealed no significant benefit when compared with the corresponding monotherapy groups.
FK778 mildly interfered with hyperacute rejection and markedly suppressed acute humoral and cellular aortic xenograft rejection. However, T-cell-dependent host responses were most potently suppressed by tacrolimus, and the overall efficacy of FK778 was similar to that of sirolimus.
本研究检测FK778方案预防异种移植排斥反应不同阶段的疗效。
在富含免疫抑制剂的人血的离体大鼠至人心超急性排斥反应不匹配灌注模型中，通过免疫荧光法检测抗体和补体组织沉积。采用仓鼠至大鼠主动脉异种移植匹配模型评估宿主细胞（淋巴细胞活化、混合淋巴细胞反应[MLR]）和体液反应性（异种抗体产生）以及组织学异种移植排斥反应。接受不同剂量的FK778、他克莫司、西罗莫司或联合方案治疗14天。
超急性排斥反应期间的抗体结合不受免疫抑制治疗的影响，但补体沉积的减少顺序如下：他克莫司＞FK778≈西罗莫司。FK778在体外最有效地降低了补体因子5。在未治疗的仓鼠主动脉异种移植大鼠中，移植体内观察到大量浸润反应，并伴有广泛的心肌细胞坏死。他克莫司＞FK778≈西罗莫司剂量依赖性地减少了异种移植浸润，且以相同顺序减少了血管壁心肌细胞坏死。他克莫司≈FK778＞西罗莫司降低了体内淋巴细胞CD25表达，他克莫司＞FK778≈西罗莫司降低了MLR。移植后几天，异种反应性IgM和IgG抗体产生水平显著上调，但他克莫司＞FK778≈西罗莫司显著降低了该水平。与相应的单药治疗组相比，联合方案未显示出显著益处。
FK778对超急性排斥反应有轻度干扰，对急性体液性和细胞性主动脉异种移植排斥反应有明显抑制作用。然而，他克莫司对T细胞依赖性宿主反应的抑制作用最强，FK778的总体疗效与西罗莫司相似。
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