Malononitrilamides 715 and 279 Prolong Rat Cardiac Allograft Survival, Reverse Ongoing Rejection, Inhibit Allospecific Antibody Production and Interact Positively with Cyclosporin
Malononitrilamides 715 and 279 Prolong Rat Cardiac Allograft Survival, Reverse Ongoing Rejection, Inhibit Allospecific Antibody Production and Interact Positively with Cyclosporin
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丙二腈酰胺 715 和 279 延长大鼠同种异体心脏移植物的存活，逆转持续的排斥反应，抑制同种异体特异性抗体的产生并与环孢菌素产生积极的相互作用
DOI：
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发表时间：
1998
影响因子：
3.7
通讯作者：
Ekberg
中科院分区：
文献类型：
--
作者：
Qi;Ekberg
A77 1726是一种丙二硝基酰胺（MNA）和来氟米特的活性代谢物，已被广泛研究并证明是一种有效的免疫抑制药物。然而，A77 1726在人体内的半衰期约为15-18天，因此，来氟米特目前主要用于自身免疫性疾病的治疗，而不是用于移植。通过寻找类似物，发现了A77 1726的衍生物MNA 715和279。这些化合物以前的实验经验仍然有限。本研究的目的是验证这些MNAs在预防和逆转排斥反应、抑制抗体产生以及与环孢素A （CsA）相互作用方面的功效。采用异位心脏移植法对大鼠进行DA ~ PVG移植。各组大鼠分别给予CsA、MNA 715或MNA 279治疗10天，从第0天或第4天开始，或不给予治疗。流式细胞术定量测定同种异体免疫球蛋白M （IgM）和免疫球蛋白G （IgG）的滴度。MNA 715或279诱导10天后，移植物存活率明显高于对照组。从第4天开始治疗，当急性排斥反应建立时，挽救了所有移植物。同种异体IgM或IgG的产生在MNA诱导过程中不存在，并且在接受MNA抢救过程的动物中被抑制。通过添加免疫调节剂喹诺酮- 3 -羧胺（Linomide®）增强移植模型，消除CsA和其他免疫抑制剂的作用。MNA和CsA联合治疗成功地克服了利诺胺的挑战，证明了两种药物的加性作用。综上所述，MNA 715和279是有效的免疫抑制剂，可预防和逆转急性同种异体移植排斥反应，抑制和抑制同种异体特异性抗体的产生，并与CsA积极相互作用。
A77 1726 is a malononitrilamide (MNA) and the active metabolite of leflunomide, which has been extensively investigated and shown to be a potent immunosuppressive drug. However, the half‐life of A77 1726 is about 15–18 days in humans and leflunomide is therefore currently being developed for the treatment of autoimmune disease and not for transplantation. Search for analogues has led to the discovery of MNA 715 and 279, derivatives of A77 1726. Previous experimental experience of these compounds is still limited. The aim of the present study was to verify the efficacy of these MNAs concerning prevention and reversal of rejection, inhibition of antibody production and interaction with cyclosporin A (CsA). Heterotopic cardiac transplantation in DA to PVG rats was used. Subgroups of rats were given either CsA, MNA 715 or MNA 279 for 10 days, starting at either day 0 or day 4, or received no treatment. Titres of allospecific immunoglobulin M (IgM) and immunoglobulin G (IgG) were quantified by flow cytometry. Ten days of induction with MNA 715 or 279 produced significantly longer graft survival than in controls. Treatment from day 4 onwards, when acute rejection was established, rescued all grafts. Allospecific production of IgM or IgG was absent during MNA induction and was suppressed in animals receiving a rescue course of MNA. The transplant model was potentiated by addition of the immunomodulator quinolone‐3‐carboxamide (Linomide®), which eliminates the effect of CsA and other immunosuppressants. The combined treatment with MNA and CsA was successful in overcoming the challenge of Linomide, demonstrating the additive effects of the two drugs. In conclusion, MNA 715 and 279 were shown to be potent immunosuppressants, preventing and reversing acute allograft rejection, inhibiting and suppressing allospecific antibody production, and the drugs interacted positively with CsA.
影响因子：
6.2
作者：
Siemasko, KF;Chong, ASF;Finnegan, A
通讯作者：
Finnegan, A
影响因子：
6.2
作者：
Chong, ASF;Rezai, K;Williams, JW
通讯作者：
Williams, JW