cyclophosphamide plus Busulfan-induced tolerance in rat into mouse xenotransplantation

环磷酰胺加白消安诱导大鼠对小鼠异种移植的耐受性

• 批准号: 13671242
• 负责人: TOMITA Yukihiro
• 金额: $ 2.37万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671242/
• 关键词: cyclophosphamide; Busulfan; tolerance; anti-alpha Gal nAb; alpha-Gal knockout mouse; xenotransplantation; hyperacute rejection; B cell tolerance; B細胞

We have recently reported a new method of cyclophosphamide(CP) plus Busulfan (BU)-induced tolerance. Recently, we could established a modified method to induce both permanent mixed chimerism and skin allograft tolerance in H-2 mismatched combinations (J Immunol 2000; 164: 34). Our present protocol consists on injection of 1 x 10^8 allogeneic spleen cells (SC) on day 0, and administration of 200mg/kg CP and 30mg/kg BU on day 2 followed by 1 x 10^7 T cell-depleted donor bone marrow cells (BMC) on day 3. As a consequence, we also found that the correlation between the establishment of mixed chimerism and skin allograft tolerance and the clonal destruction as the major mechanisms of tolerance induction. In the present study, we applied our new system to rat into mouse xenograft tolerance. Mixed chimerism was detectable (5-20%) at 2-8 weeks after treatments, and F344 rat skins were significantly and specifically prolonged (median 40 days, max 75 days). However, neither permanent mixed chimerism nor skin xenograft tolerance could not be induced. NK cell-depletion did not permit more profound degree of mixed chimerism or induce more skin graft prolongation.. The present study indicated that our new protocol can induce temporal mixed chimerism and moderate skin graft polongation in a donor specific manner.

我们最近报道了一种环磷酰胺（CP）加白消安（BU）诱导耐受的新方法。最近，我们建立了一种改良的方法，在H-2错配组合中诱导永久性混合嵌合体和皮肤同种异体移植物耐受（J Immunol 2000; 164：34）。我们目前的方案包括在第0天注射1 × 10^8个同种异体脾细胞（SC），在第2天给予200 mg/kg CP和30 mg/kg BU，然后在第3天给予1 × 10^7个T细胞耗尽的供体骨髓细胞（BMC）。因此，我们还发现混合嵌合体的建立与皮肤移植耐受之间的相关性以及克隆破坏是耐受诱导的主要机制。在本研究中，我们将我们的新系统应用于大鼠到小鼠异种移植耐受。在处理后2-8周可检测到混合嵌合体（5-20%），F344大鼠皮肤显著且特异性延长（中位数40天，最长75天）。然而，无论是永久性的混合嵌合体，也不能诱导皮肤异种移植耐受。NK细胞耗竭不允许更深程度的混合嵌合体或诱导更多的皮肤移植延长。目前的研究表明，我们的新方案可以诱导暂时的混合嵌合体和适度的皮肤移植物延长在供体特异性的方式。

项目成果

Shimizu, I., Y.Tomita, T.Iwai, G.Matsuzaki, K.Nomoto et al.: "Different expressions of Ly-49 receptors on mouse NK and NK cells"Immunobiology. 204. 466-476 (2001)

Shimizu, I., Y.Tomita, T.Iwai, G.Matsuzaki, K.Nomoto 等：“小鼠 NK 和 NK 细胞上 Ly-49 受体的不同表达”免疫生物学。

Iwai, T, Y.Tomita, Q-W Zhang, S.Okano, I.Shimizu, R.Minagawa et al.: "The Requirement of higher degree of chimerism for the induction of skin allograft tolerance in cyclophosphamide-induced tolerance"Transplant.Int.. (In press).

Iwai，T，Y.Tomita，Q-W Zhang，S.Okano，I.Shimizu，R.Minakawa 等：“在环磷酰胺诱导的耐受中诱导皮肤同种异体移植耐受需要更高程度的嵌合”Transplant.Int

Shimizu, I., Y.Tomita, H.Yasui: "Induction of B cell tolerance against Gal-alpha(1-3) Gal Ag in cyclophosphamide (CP)-induced tolerance"Transplantation (Supp.). 74(4). 316 (2002)

Shimizu, I.、Y.Tomita、H.Yasui：“在环磷酰胺 (CP) 诱导的耐受中诱导 B 细胞对 Gal-α(1-3) Gal Ag 的耐受”移植（增刊）。

Tomita, Y., Q-W.Zhang, I.Shimizu, T.Iwai, S.Okano, K.Nomoto et al.: "Fractionated dosing of cyclophosphamide prevents leucopenic side effects in cyclophosphamide-induced tolerance"Surg.Today. (In press).

Tomita, Y.、Q-W.Zhang、I.Shimizu、T.Iwai、S.Okano、K.Nomoto 等人：“环磷酰胺的分次给药可预防环磷酰胺诱导的耐受性中白细胞减少的副作用”Surg.Today。

Tomita, Y., Q-W. Zhang, I. Shimizu, T. Iwai, S. Okano, K. Nomoto et al: "Fractionated dosing of cyclophosphamide prevents leucopenic side effects in cyclophosphamide-induced tolerance."Surg. Today. In press.

富田，Y.，Q-W。