使用云南眼镜蛇毒因子清除补体延长预致敏大鼠同种心脏移植的存活
摘要
目的研究云南眼镜蛇毒因子(Y-CVF)清除大鼠体内补体和对预致敏大鼠同种心脏移植急性体液排斥反应的作用。
方法Brown-Norway(BN)大鼠皮肤连续3次移植到Lewis大鼠。采用微量淋巴毒试验检测Lewis大鼠体内抗BN大鼠特异性抗体。建立稳定的预致敏Lewis大鼠。随后将BN大鼠心脏移植给预致敏Lewis大鼠,采用颈部异位心脏移植建立同种急性体液排斥反应模型。15对大鼠随机分成2组,(1)Y-CVF组(n=8)于心脏移植前24h静脉给予Y-CVF 80μg/kg,(2)对照组(n=7)心脏移植前不用Y-CVF。观察移植心的生存时间,移植心停跳后病理学检查排斥反应类型,免疫组化染色观察移植心IgG和补体C3的沉积。
结果Lewis大鼠预致敏后抗BN大鼠抗体滴度由0升高至1∶1 028~1∶2056。Y-CVF治疗组移植心存活时间(99.50±38.72h)较对照组(12.71±13.94h)显著延长(t=5.599,p<0.001)。病理检查结果证实Y-CVF组均未发生急性体液性排斥反应,仅见细胞排斥反应为主的急性排斥反应的病理特征;IgG沉积为阳性而补体C3的沉积为阴性。对照组则见急性体液排斥反应的病理特征,可见大量的中性粒细胞浸润和小血管内血栓形成,IgG和补体C3的沉积均为阳性。
结论Y-CVF通过耗竭受鼠体内补体,可克服预致敏大鼠同种心脏移植急性体液排斥反应的发生,显著延长移植心的存活时间。作为以补体为靶目标的药物,对临床上存在预存抗体的高敏患者,移植前使用Y-CVF预处理有进一步研究的价值。
Objective Study the effects of Y-CVF on depleting complement in vivo and prolonging allograft survival in acute humoral rejection rat cardiac allograft rejection model. Methods Allograft Lewis rats were presensitized by sequential grafting of three full-thickness Brown-Norway rats skin grafts. Then presensitized Lewis rats received a heterotopic Brown-Norway cardiac allograft. Serum elicit cytotoxic alloantibody titers of Lewis rat were determined by a modified in vitro complement-dependent microcytotoxicity assay. Fifteen recipient rats were randomly divided into control group: rats untreated (n=7) and test group: rats was administered by i.v. injection with a single dose of 0.08 mg/kg CVF (n=8) on day -1. Anticomplementary activity of the Y-CVF in vivo was measured by CH50. As cessation of graftbeat, allograft rejection was confirmed by tissue pathology and immunohistochemistry examination. Results After presensitized serum elicit cytotoxicantibody titer of Lewis rats raised prominently from 0 to 1∶1 028~1∶2056. A single dose of Y-CVF (0.08mg/kg) eliminated complement activity to an undetectable level 24 h after administration. The survival time of graft was significantly prolonged to 99.50±38.72 h in rats received CVF, compared with a rejection time of 12.71±13.94 h in untreated rats (t=5.599, P <0.001). Histology of rejected allografts from untreated group animals generally revealed the features of acute humoral rejection, including intravascular thrombosis, myocardial necrosis, interstitial hemorrhage and edema,intense infiltration that were primary composed of granulocytes. The allografts rejected in CVF treated rats demonstrated histopathologic feature of acute rejection with extensive cellular infiltration with mononuclear cells, myocardial necrosis. Immunohistochemistry demonstrated deposition of IgG in treatment group as well as in control group. Deposition of C3 was only found in control group. Conclusion Our study demonstrated administration of CVF can overcome acute humoral rejection in models of presensitized rat cardiac allotransplantation. Y-CVF showed potentially capacity to use in clinical transplantation across ABO incompatible and positive cross-match barriers.
方法Brown-Norway(BN)大鼠皮肤连续3次移植到Lewis大鼠。采用微量淋巴毒试验检测Lewis大鼠体内抗BN大鼠特异性抗体。建立稳定的预致敏Lewis大鼠。随后将BN大鼠心脏移植给预致敏Lewis大鼠,采用颈部异位心脏移植建立同种急性体液排斥反应模型。15对大鼠随机分成2组,(1)Y-CVF组(n=8)于心脏移植前24h静脉给予Y-CVF 80μg/kg,(2)对照组(n=7)心脏移植前不用Y-CVF。观察移植心的生存时间,移植心停跳后病理学检查排斥反应类型,免疫组化染色观察移植心IgG和补体C3的沉积。
结果Lewis大鼠预致敏后抗BN大鼠抗体滴度由0升高至1∶1 028~1∶2056。Y-CVF治疗组移植心存活时间(99.50±38.72h)较对照组(12.71±13.94h)显著延长(t=5.599,p<0.001)。病理检查结果证实Y-CVF组均未发生急性体液性排斥反应,仅见细胞排斥反应为主的急性排斥反应的病理特征;IgG沉积为阳性而补体C3的沉积为阴性。对照组则见急性体液排斥反应的病理特征,可见大量的中性粒细胞浸润和小血管内血栓形成,IgG和补体C3的沉积均为阳性。
结论Y-CVF通过耗竭受鼠体内补体,可克服预致敏大鼠同种心脏移植急性体液排斥反应的发生,显著延长移植心的存活时间。作为以补体为靶目标的药物,对临床上存在预存抗体的高敏患者,移植前使用Y-CVF预处理有进一步研究的价值。
Objective Study the effects of Y-CVF on depleting complement in vivo and prolonging allograft survival in acute humoral rejection rat cardiac allograft rejection model. Methods Allograft Lewis rats were presensitized by sequential grafting of three full-thickness Brown-Norway rats skin grafts. Then presensitized Lewis rats received a heterotopic Brown-Norway cardiac allograft. Serum elicit cytotoxic alloantibody titers of Lewis rat were determined by a modified in vitro complement-dependent microcytotoxicity assay. Fifteen recipient rats were randomly divided into control group: rats untreated (n=7) and test group: rats was administered by i.v. injection with a single dose of 0.08 mg/kg CVF (n=8) on day -1. Anticomplementary activity of the Y-CVF in vivo was measured by CH50. As cessation of graftbeat, allograft rejection was confirmed by tissue pathology and immunohistochemistry examination. Results After presensitized serum elicit cytotoxicantibody titer of Lewis rats raised prominently from 0 to 1∶1 028~1∶2056. A single dose of Y-CVF (0.08mg/kg) eliminated complement activity to an undetectable level 24 h after administration. The survival time of graft was significantly prolonged to 99.50±38.72 h in rats received CVF, compared with a rejection time of 12.71±13.94 h in untreated rats (t=5.599, P <0.001). Histology of rejected allografts from untreated group animals generally revealed the features of acute humoral rejection, including intravascular thrombosis, myocardial necrosis, interstitial hemorrhage and edema,intense infiltration that were primary composed of granulocytes. The allografts rejected in CVF treated rats demonstrated histopathologic feature of acute rejection with extensive cellular infiltration with mononuclear cells, myocardial necrosis. Immunohistochemistry demonstrated deposition of IgG in treatment group as well as in control group. Deposition of C3 was only found in control group. Conclusion Our study demonstrated administration of CVF can overcome acute humoral rejection in models of presensitized rat cardiac allotransplantation. Y-CVF showed potentially capacity to use in clinical transplantation across ABO incompatible and positive cross-match barriers.
引文
1. Sackner-bernstein JD, Godin S. Increasing organ transplantation- fairly.Transplantation,200477(1):157–161.
2. Lieber MM, Sherr CJ, Benveniste RE, et al. Biologic and immunologic properties of porcine type Cviruses. Virology, 1975, 66:616–619.
3. Muller—Eberhard HJ.Isolation of the anticomp]ementary protein from cobra Venom and its mode of action on C3. J Immunol, 1971,107:1666
4. Leventhal JR,Dalmasso AP,Cromwell JM,et a1.Prolongation of cardiac xenograft survival by depletion of complement.Transplantation,1993;55: 857–866.
5. Candinas D,Lesnikoski BA,Robson SC,et a1.Effect of repetitive high—dose treatment with soluble complement receptor type 1 and cobra venom factor on discordant xenograft survival.Transplantation, 1996;62:336–342.
6. Qian-Yun Sun, Gang Chen, Hui Guo, et al. Prolonged cardiac xenograft survival in guinea pig-to-rat model by a highly active cobra venom factor. Toxicon, 2003; 42:257–262.
7. Chen G, Sun QY, Wang XM, et al. Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants. Xenotransplantation, 2004; 11:123-32.
8. Guttmann RD. Genetics of acute rejection of rat cardiac allografts and a model of hyperacute rejection. Transplantation 1974;17(4):383-386.
9. Chen ZH. A technique of cervical heterotopic heart transplantation in mice. Transplantation 1991; 52(6):1099-1101.
10. Terasaki PZ, McCllelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964; 204:998-1000
11. Ballow M,Cochrane CG. Two anticomplementary factors in cobra venom:hemolysis og guinea pig erythrocytes by one of them.J Immunology,1969,103:944-952.
12. 孙黔云, 王婉瑜, 熊郁良. 眼镜蛇毒高活性抗补体因子的体外溶血活性研究. 中国药理学通报,2003,19:909–913
13. Taylor CJ, Chapman JR, Ting A, and Morris PJ. Characterization of lymphocytotoxic antibodies causing a positive crossmatch in renal transplantation. Relationship to primary and regraft outcome. Transplantation 1989; 48: 953–959
14. Glotz D; Antoine C; Duboust A. Antidonor Antibodies and Transplantation: How to Deal with Them Before and After Transplantation.Transplantation, 2005;79 suppl:S30-S32
15. Solange M, Manuel Pascual. Humoral rejection of organ allografts. Am J Transplant, 2005, 5:2611–2618.
1. Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS. Humoral antibodies in renal allotransplantation in man. N Engl JMed 1970; 282: 111.
2. Gérard R, Christiane M, Laurent M, et al. Donor-Specific Antibodies in Allograft Rejection: Clinical and Experimental Data. Transplantation. 2005;79(Suppl 3): S14.
3. Cerny A, Ramseier H, Bazin H, et al. Unimpaired first-set and second-set skin graft rejection in agammaglobulinemic mice. Transplantation 1988; 45: 1111.
4. Alexander DZ, Pearson TC, Hendrix R, et al. Analysis of effector mechanisms in murine cardiac allograft rejection. Transpl Immunol 1996; 4: 46.
5. Br(?)ndle D, Joergensen J, Zenke G, et al. Contribution of donor-specific antibodies to acute allograft rejection. Evidence from B cell-deficient mice. Transplantation 1998; 65:1489.
6. Wasowska BA, Qian Z, Cangello DL, et al. Passive transfer of alloantibodies restores acute cardiac rejection in IgKO mice. Transplantation 2001; 71: 727.
7. Lunsford KE, Horne PH, Wang Y, et al. Role of alloantibody in CD4+ T cell dependent immune damage of hepatocytes. Am J Transplant 2004; 4(suppl 8): 457 .
8. Russell PS, Chase CM, Winn HJ, et al. Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol 1994; 152: 5135 .
9. Russell PS, Chase CM, Colvin RB. Alloantibody and T cell-mediated immunity in the pathogenesis of transplant arteriosclerosis: lack of progression to sclerotic lesions in B cell-deficient mice. Transplantation 1997; 64: 1531.
10. Shi C, Lee WS, He Q, et al. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci USA 1996; 93: 4051.
11. Feucht HE, Schneeberger H, Hillebrand G et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int 1993; 43: 1333.
12. Lederer SR, Kluth-Pepper B, Schneeberger H, Albert E, Land W, Feucht HE. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001; 59: 334.
13. Lederer SR, Kluth-Pepper B, Schneeberger H, et al. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001;59: 334.
14. Herzenberg AM, Gill JS, Djurdjev O, et al. C4d deposition in acute rejection: an independent long-term prognostic factor. J AmSoc Nephrol 2002; 13: 234–241.
15. Regele H, Exner M, Watschinger B et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol Dial Transplant 2001; 16: 2058–2066.
16. Mauiyyedi S, Crespo M, Collins AB et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology and pathologic classification. J Am Soc Nephrol 2002; 13: 779–787.
17. McKenna RM, Takemoto SK, Terasaki PI. Anti HLA antibodies after solid organ transplantation. Transplantation 2000; 69: 319.
18. Jaramillo A, Smith MA, Phelan D et al. Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation 1999; 67: 1155.
19. Chan L, Terasaki PI, El-Awar N, Pokaiyayanichkul T, Kam I. Chronic failure after 3 years predicted by presence of Class II HLA antibodies. Am J Transplant 2002; 2 (Suppl. 3): 407.
20. Lee PC, Terasaki PI, Takemoto SK et al. All chronic rejection failures of kidney transplants preceded by development of HLA antibodies. Transplantation 2002; 74: 1192.
21. Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003; 3: 665.
22. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000; 70: 887.
23. Rocha PN, Butterly DW, Greenberg A, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003; 75: 1490.
24. Theruvath TP, Saidman SL, Mauiyyedi S, et al. Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001; 72: 77.
25. Pascual M, Sadman S, Tollkof-Rubin N, et al Plasmic exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. Transplantation 1998;66:1460.
26. Jolles S. A review of high - dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin Exp Dermatol 2001 , 26 :127 .
27. Robinson JA, Radvany RM, Mullen MG, et al . Plasmapheresis followed by intravenous immunoglobulin in presensitized patients awaiting thoracicorgan transplantation. Ther Apher 1997, 1: 147 .
28. Hohn R, Lietz K, Burke E, et al. Intravenous immunoglobulin reduces anti—HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation 1999 ,100 (19 suppl) :229.
29. Buhler L, Pidwell D ,Dowling RD ,et al . Different responses of human anti - HLAand anti - alphagal antibody to long - term intravenous immunoglobulin therapy. Xenotransplantation 1999; 6: 181.
30. Glotz, D, Antoine C, Julia P, et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transplant 2002; 2: 758.
31. Jordan SC, Tyan DB, Stablein DM, et al. Evaluation of intravenous immunoglobulin (IVIg) as an agent to lower allosensitization and improve transplantation in highly-sensitized adult ESRD patients: report of the NIH IG02 trial. In American Transplant Congress. 2003. Washington, D.C.
32. SieversTM,Rossi SJ,Ohobrial RM,et al.Mycophenolate mofetil.Pharmacotherapy 1997;17:1178.
33. Theruvath TP, Delmonico FL, Saidman S, et al. long-term outcome after treatment of early refractory acute humoral rejection in kidney transplantation. Am J Transplant, 2001; 1(suppl 1): 151.
34. Lin Y, Sobis H, Vandeputte M, et al. Long-term xenograft survival and suppression of xenoantibody formation in the hamster-to-rat heart transplant model using a combination therapy of leflunomide and cyclosporine. Transplant Proc, 1994;26(6):3202.
35. Williams JW, Xiao F, Foster PF, et al. Immunosuppressive effects of leflunomide in a cardiac allograft model. Transplant Proc, 1993; 25(1 Pt 1):745.
36. Xiao F, Chong AS, Foster P, et al. Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation, 1994; 58(7):828.
37. Morris RE, Huang X, Cao W, et al. Leflunomide (HWA486) and its analog supress Tand B-cell proliferation in vitro, acute rejection, ongoing rejection, and antidonor antibody synthesis in mouse, rat, and cynomolgus monkey transplant recipients as well as arterial intimal thickening after ballon catheter injury. Transplant Proc, 1995; 27: 445.
38. Siemasko KF, Chong AS, Williams JW, et al. Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation, 1996; 61: 635.
39. Lin Y, Vandeputte M, Waer M. Effect of leflunomide on T-cell dependent xenoantibody formation in rats receiving hamster heart xenografts. Transplant Proc 1996; 28: 925.
40. Lin Y, Waer M. In vivo mechanism of action of leflunomide: selective inhibition of the capacity of B lymphocytes to make T- independent xenoantibodies. Transplant Proc 1996; 28: 3085.
41. Williams JW, Xiao F, Foster P, et al. Leflunomide in experimental transplantation. Transplantation 1994; 57(8): 1223.
42. Grillo-Lopez AJ. Rituximab: an insider’s historical perspective. Semin Oncol 2000; 27 (6 Suppl 12):9.
43. Gloor JM, DeGoey SR, Pineda AA, et al. Overcoming a positive crossmatch in living-donor kidney transplantation. Am J Transplant 2003; 3(8): 1017.
44. Gloor JM, DeGoey SR, Griffin MD, et al. Living donor kidney transplantation with and without splenectomy in positive crossmatch patients. American Transplant Congress 2004. Boston, MA. Abstract 364.
2. Lieber MM, Sherr CJ, Benveniste RE, et al. Biologic and immunologic properties of porcine type Cviruses. Virology, 1975, 66:616–619.
3. Muller—Eberhard HJ.Isolation of the anticomp]ementary protein from cobra Venom and its mode of action on C3. J Immunol, 1971,107:1666
4. Leventhal JR,Dalmasso AP,Cromwell JM,et a1.Prolongation of cardiac xenograft survival by depletion of complement.Transplantation,1993;55: 857–866.
5. Candinas D,Lesnikoski BA,Robson SC,et a1.Effect of repetitive high—dose treatment with soluble complement receptor type 1 and cobra venom factor on discordant xenograft survival.Transplantation, 1996;62:336–342.
6. Qian-Yun Sun, Gang Chen, Hui Guo, et al. Prolonged cardiac xenograft survival in guinea pig-to-rat model by a highly active cobra venom factor. Toxicon, 2003; 42:257–262.
7. Chen G, Sun QY, Wang XM, et al. Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants. Xenotransplantation, 2004; 11:123-32.
8. Guttmann RD. Genetics of acute rejection of rat cardiac allografts and a model of hyperacute rejection. Transplantation 1974;17(4):383-386.
9. Chen ZH. A technique of cervical heterotopic heart transplantation in mice. Transplantation 1991; 52(6):1099-1101.
10. Terasaki PZ, McCllelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964; 204:998-1000
11. Ballow M,Cochrane CG. Two anticomplementary factors in cobra venom:hemolysis og guinea pig erythrocytes by one of them.J Immunology,1969,103:944-952.
12. 孙黔云, 王婉瑜, 熊郁良. 眼镜蛇毒高活性抗补体因子的体外溶血活性研究. 中国药理学通报,2003,19:909–913
13. Taylor CJ, Chapman JR, Ting A, and Morris PJ. Characterization of lymphocytotoxic antibodies causing a positive crossmatch in renal transplantation. Relationship to primary and regraft outcome. Transplantation 1989; 48: 953–959
14. Glotz D; Antoine C; Duboust A. Antidonor Antibodies and Transplantation: How to Deal with Them Before and After Transplantation.Transplantation, 2005;79 suppl:S30-S32
15. Solange M, Manuel Pascual. Humoral rejection of organ allografts. Am J Transplant, 2005, 5:2611–2618.
1. Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS. Humoral antibodies in renal allotransplantation in man. N Engl JMed 1970; 282: 111.
2. Gérard R, Christiane M, Laurent M, et al. Donor-Specific Antibodies in Allograft Rejection: Clinical and Experimental Data. Transplantation. 2005;79(Suppl 3): S14.
3. Cerny A, Ramseier H, Bazin H, et al. Unimpaired first-set and second-set skin graft rejection in agammaglobulinemic mice. Transplantation 1988; 45: 1111.
4. Alexander DZ, Pearson TC, Hendrix R, et al. Analysis of effector mechanisms in murine cardiac allograft rejection. Transpl Immunol 1996; 4: 46.
5. Br(?)ndle D, Joergensen J, Zenke G, et al. Contribution of donor-specific antibodies to acute allograft rejection. Evidence from B cell-deficient mice. Transplantation 1998; 65:1489.
6. Wasowska BA, Qian Z, Cangello DL, et al. Passive transfer of alloantibodies restores acute cardiac rejection in IgKO mice. Transplantation 2001; 71: 727.
7. Lunsford KE, Horne PH, Wang Y, et al. Role of alloantibody in CD4+ T cell dependent immune damage of hepatocytes. Am J Transplant 2004; 4(suppl 8): 457 .
8. Russell PS, Chase CM, Winn HJ, et al. Coronary atherosclerosis in transplanted mouse hearts. II. Importance of humoral immunity. J Immunol 1994; 152: 5135 .
9. Russell PS, Chase CM, Colvin RB. Alloantibody and T cell-mediated immunity in the pathogenesis of transplant arteriosclerosis: lack of progression to sclerotic lesions in B cell-deficient mice. Transplantation 1997; 64: 1531.
10. Shi C, Lee WS, He Q, et al. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci USA 1996; 93: 4051.
11. Feucht HE, Schneeberger H, Hillebrand G et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int 1993; 43: 1333.
12. Lederer SR, Kluth-Pepper B, Schneeberger H, Albert E, Land W, Feucht HE. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001; 59: 334.
13. Lederer SR, Kluth-Pepper B, Schneeberger H, et al. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001;59: 334.
14. Herzenberg AM, Gill JS, Djurdjev O, et al. C4d deposition in acute rejection: an independent long-term prognostic factor. J AmSoc Nephrol 2002; 13: 234–241.
15. Regele H, Exner M, Watschinger B et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol Dial Transplant 2001; 16: 2058–2066.
16. Mauiyyedi S, Crespo M, Collins AB et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology and pathologic classification. J Am Soc Nephrol 2002; 13: 779–787.
17. McKenna RM, Takemoto SK, Terasaki PI. Anti HLA antibodies after solid organ transplantation. Transplantation 2000; 69: 319.
18. Jaramillo A, Smith MA, Phelan D et al. Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation 1999; 67: 1155.
19. Chan L, Terasaki PI, El-Awar N, Pokaiyayanichkul T, Kam I. Chronic failure after 3 years predicted by presence of Class II HLA antibodies. Am J Transplant 2002; 2 (Suppl. 3): 407.
20. Lee PC, Terasaki PI, Takemoto SK et al. All chronic rejection failures of kidney transplants preceded by development of HLA antibodies. Transplantation 2002; 74: 1192.
21. Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003; 3: 665.
22. Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000; 70: 887.
23. Rocha PN, Butterly DW, Greenberg A, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003; 75: 1490.
24. Theruvath TP, Saidman SL, Mauiyyedi S, et al. Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001; 72: 77.
25. Pascual M, Sadman S, Tollkof-Rubin N, et al Plasmic exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation. Transplantation 1998;66:1460.
26. Jolles S. A review of high - dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin Exp Dermatol 2001 , 26 :127 .
27. Robinson JA, Radvany RM, Mullen MG, et al . Plasmapheresis followed by intravenous immunoglobulin in presensitized patients awaiting thoracicorgan transplantation. Ther Apher 1997, 1: 147 .
28. Hohn R, Lietz K, Burke E, et al. Intravenous immunoglobulin reduces anti—HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation 1999 ,100 (19 suppl) :229.
29. Buhler L, Pidwell D ,Dowling RD ,et al . Different responses of human anti - HLAand anti - alphagal antibody to long - term intravenous immunoglobulin therapy. Xenotransplantation 1999; 6: 181.
30. Glotz, D, Antoine C, Julia P, et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transplant 2002; 2: 758.
31. Jordan SC, Tyan DB, Stablein DM, et al. Evaluation of intravenous immunoglobulin (IVIg) as an agent to lower allosensitization and improve transplantation in highly-sensitized adult ESRD patients: report of the NIH IG02 trial. In American Transplant Congress. 2003. Washington, D.C.
32. SieversTM,Rossi SJ,Ohobrial RM,et al.Mycophenolate mofetil.Pharmacotherapy 1997;17:1178.
33. Theruvath TP, Delmonico FL, Saidman S, et al. long-term outcome after treatment of early refractory acute humoral rejection in kidney transplantation. Am J Transplant, 2001; 1(suppl 1): 151.
34. Lin Y, Sobis H, Vandeputte M, et al. Long-term xenograft survival and suppression of xenoantibody formation in the hamster-to-rat heart transplant model using a combination therapy of leflunomide and cyclosporine. Transplant Proc, 1994;26(6):3202.
35. Williams JW, Xiao F, Foster PF, et al. Immunosuppressive effects of leflunomide in a cardiac allograft model. Transplant Proc, 1993; 25(1 Pt 1):745.
36. Xiao F, Chong AS, Foster P, et al. Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation, 1994; 58(7):828.
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