LAIR-1（CD305）与器官移植相关性的研究
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摘要
1983年Burns等在研究NK细胞杀伤机制的过程中,用从人外周血分离的NK细胞免疫小鼠,得到一株单克隆抗体9.1C3,并发现它能够显著抑制NK细胞对K562细胞的杀伤。1997年Meyaard成功克隆其基因,并命名为白细胞相关免疫球蛋白样受体1(leukocyte-associated immunoglobulin-like recepter-1,LAIR-1)。2004年12月在第八届国际人类白细胞分化抗原会议(HLDA8)上,第四军医大学金伯泉教授与英国牛津大学和澳大利亚纽卡绍尔大学的学者合作提交单克隆抗体,LAIR-1被命名为新的人类白细胞分化抗原CD305。
LAIR-1基因位于人染色体19q13.4上的白细胞免疫球蛋白样受体复合物(leukocyte Ig-like receptor complex,LRC)内,其分子胞膜外区包含有1个免疫球蛋白样结构域,胞浆区含有2个ITIM基序,可募集SHP-1。LAIR-1广泛表达于多种免疫细胞上,包括NK细胞、B细胞、T细胞、单核细胞、树突状细胞及胸腺细胞等。体外研究表明,LAIR-1被其相应的mAb交联后,可传递强烈的抑制性信号,可抑制包括NK细胞、效应T细胞、B细胞和树突状细胞前体等多种免疫细胞的功能。
本实验应用双单克隆抗体夹心ELISA方法对临床器官移植标本sLAIR-1进行检测。在正常人血清和血浆中检测到sLAIR-1分子的存在,比较了血清及血浆中sLAIR-1的含量。在肝、肾移植围手术期患者血清中检测sLAIR-1的变化,并应用流式细胞技
LAIR-1/9.1C3 was first discovered in 1983 by Burns' group based on the monoclonal antibody 9.1C3 raised by immunizing mice with human natural killer (NK) cells and its function that 9.1C3 mAb could inhibit the killing of NK cells against K562 cells. The LAIR-1 gene was cloned in 1997 and was named leukocyte associated immunoglobulin-like recepter-1 (LAIR-1) by Meyaard. During the 8~(th) international Human Leucocyte Differentiation Antigen Congress held in Dec 2004, LAIR-1 was named CD305 as a novel HLDA after its mAb was referred together by Professor Jin Bo-quan of the Fourth Military Medical University (China) and other experts from Oxford University (Britain) and The University of Newcastle (Australian).The gene of LAIR-1 was confirmed to be located within the leukocyte Ig-like receptor complex (LRC) on human chromosome 19q13.4. Its extracellular region contains a single Ig-like domain, whereas the cytoplasmic region contains two immunoreceptor tyrosine-based inhibitouy motifs (ITlMs) which can recruit SHP-1. LAIR-1 is expressed generally on many kinds of immunocells including NK cells, T cells, B cells, dendritic cells
and thymus cells. It has been proved in vitro that cross-linking of LAIR-1/9.1C3 by mAb delivers an intensive inhibitory signal which is capable of inhibiting the functions of NK cells, T cells, B cells and dendritic cell precursors.In this experiment, we used the double mAb sandwich ELISA for detecting the level of sLAIR-1 in samples from clinical organ transplantation patients.The sLAIR-1 molecules were detected to exist in serum and plasma of healthy people, and the content was compared between them. In the after operation time of liver transplantation and kidney transplantation, change of sLAIR-1 was examined and was compared with the expression of mLAIR-1 which was detected by flow cytometry. It was found that the level of sLAIR-1 in allograft patients was significantly higher than healthy people and the level of sLAIR-1 was related with the state and stage of these diseases, whereas mLAIR-1 showed the opposite trend. The serum level of sLAIR-1 dramatically rose in the patients who had opposite accidents after liver and kidney transplantation.lt was the 1st time that we detected sLAIR-1 in the bile which outweighed other transplantation immunity associated cytokines on judging rejection and it also had excellent correlation.Our work may contribute to the following study on immune regulation effect and clinical immune apply of sLAIR-1.
LAIR-1基因位于人染色体19q13.4上的白细胞免疫球蛋白样受体复合物(leukocyte Ig-like receptor complex,LRC)内,其分子胞膜外区包含有1个免疫球蛋白样结构域,胞浆区含有2个ITIM基序,可募集SHP-1。LAIR-1广泛表达于多种免疫细胞上,包括NK细胞、B细胞、T细胞、单核细胞、树突状细胞及胸腺细胞等。体外研究表明,LAIR-1被其相应的mAb交联后,可传递强烈的抑制性信号,可抑制包括NK细胞、效应T细胞、B细胞和树突状细胞前体等多种免疫细胞的功能。
本实验应用双单克隆抗体夹心ELISA方法对临床器官移植标本sLAIR-1进行检测。在正常人血清和血浆中检测到sLAIR-1分子的存在,比较了血清及血浆中sLAIR-1的含量。在肝、肾移植围手术期患者血清中检测sLAIR-1的变化,并应用流式细胞技
LAIR-1/9.1C3 was first discovered in 1983 by Burns' group based on the monoclonal antibody 9.1C3 raised by immunizing mice with human natural killer (NK) cells and its function that 9.1C3 mAb could inhibit the killing of NK cells against K562 cells. The LAIR-1 gene was cloned in 1997 and was named leukocyte associated immunoglobulin-like recepter-1 (LAIR-1) by Meyaard. During the 8~(th) international Human Leucocyte Differentiation Antigen Congress held in Dec 2004, LAIR-1 was named CD305 as a novel HLDA after its mAb was referred together by Professor Jin Bo-quan of the Fourth Military Medical University (China) and other experts from Oxford University (Britain) and The University of Newcastle (Australian).The gene of LAIR-1 was confirmed to be located within the leukocyte Ig-like receptor complex (LRC) on human chromosome 19q13.4. Its extracellular region contains a single Ig-like domain, whereas the cytoplasmic region contains two immunoreceptor tyrosine-based inhibitouy motifs (ITlMs) which can recruit SHP-1. LAIR-1 is expressed generally on many kinds of immunocells including NK cells, T cells, B cells, dendritic cells
and thymus cells. It has been proved in vitro that cross-linking of LAIR-1/9.1C3 by mAb delivers an intensive inhibitory signal which is capable of inhibiting the functions of NK cells, T cells, B cells and dendritic cell precursors.In this experiment, we used the double mAb sandwich ELISA for detecting the level of sLAIR-1 in samples from clinical organ transplantation patients.The sLAIR-1 molecules were detected to exist in serum and plasma of healthy people, and the content was compared between them. In the after operation time of liver transplantation and kidney transplantation, change of sLAIR-1 was examined and was compared with the expression of mLAIR-1 which was detected by flow cytometry. It was found that the level of sLAIR-1 in allograft patients was significantly higher than healthy people and the level of sLAIR-1 was related with the state and stage of these diseases, whereas mLAIR-1 showed the opposite trend. The serum level of sLAIR-1 dramatically rose in the patients who had opposite accidents after liver and kidney transplantation.lt was the 1st time that we detected sLAIR-1 in the bile which outweighed other transplantation immunity associated cytokines on judging rejection and it also had excellent correlation.Our work may contribute to the following study on immune regulation effect and clinical immune apply of sLAIR-1.
引文
1. Bums GF, Triglia T, Bartlett PF, et al. Human natural killer cells, activated lymphocyte killer cells, and monocytes possess simlar cytotoxic mechanisms [J]. PANS 1983;80: 7606.
2. Meyaa L, Adema G J, Chang C, et al.LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocyte[J].Immunity 1997;7: 283.
3. Xu MI, Zhao RX, Zhao ZJ, et al. Identification and characterization of leukocyteassociated Ig-like receptor-1 as a major anchor Protein of tyrosine phosphatase SHP-1 in hematopoietic cells [J]. J Biol Chem 2000;275: 17440.
4. Sathish JG, Johnson KG, FullerK J, et al. Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells [J]. J Immunol 2001;166: 1763.
5. Van der Vuurst de Vrices AR, Clevers H, Lontenberg T, et al.Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling[J].Eur J Immunol 1999;29:3160.
6. Poggi A, Pellegatta F, Leone BE, et al. Engagement of the leukocyte-associated Ig-like receptor-1 induces programmed cell death and prevents NF-kappaB nuclear translocation in human myeloid leukemias [J].Eur J Immunol 2000;30: 2751.
7. Zocchi MR, Pellegatta F, Pierri I, et al. Leukocyte-associated Ig-like receptor-1 prevents granulocyte-monocyte colony stimulating factor-depedent proliferation and Akt1/PKB alpha activation in primary acute myeloid leukemia cells[J]. Eur J Immunol 2001;31: 3667.
8. Saverino D, Fabbi M, Merlo A, Ravera G, Grossi CE, Ciccone E. Surface density expression of the leukocyte-associated Ig-like receptor-1 is directly related to inhibition of human T-cell functions. Hum Immunol 2002;Jul, 63(7): 534-46.
9.薛江南,欧阳为明,贾卫,等.夹心ELISA检测可溶型LAIR—1方法的建立及其应用的研究.上海免疫学杂志 2003;23(4):268.
10. Butscher WG, Powers C, Olive M, et al. Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/ CREB2. J Biol Chem 1998;273:552 -560.
11. Lebbink RJ, Ruiter T, Verbrugge A, et al.The mouse homologue of the leukocyte- associated Ig-like receptor-1 is an inhibitory receptor that recuits Src homology region 2-containing protein tyrosine phosphatase (SHP)-2, but not SHP-1[J]. J Immunol 2004;172: 5535-5543.
12. Vuurst VAR, Clevers H, Logtenberg T, et al.Leukocyte-associated Ig-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling[J].Eur J Immunol 1999;29:3160-3167.
13. De Milito A, Nilsson A, Titanji K, et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004;Mar, 15;103(6): 2180-6.
14. Poggi A, Tomasello E, Ferrero E, et al.p40/LAIR-l regulates the differentiation of peripheral blood precursors to dendritic cells induced by granulocyte-monocyte colony- stimulating factor[J].Eur J Immunol 1998;28:2086-2091.
15. Establishment of an ELISA system for determining soluble LAIR-1 levels in sera of patients with HFRS and kidney transplant. Journal of Immunological Methods 2004;292: 109-117.
16. Bazil V. Physiological enzymatic cleavage of leukocyte membrane molecules. Immunology Today 1995;16:135-140.
17. Hooper NM, Karran EH and Turner AJ. Membrane protein secretase. J Bio Chem 1997;321(pt2): 265-279.
18. Yammamoto S, Higuchi Y, Y oshiyama K, et al. ADAM family proteins in the immune system. Immunology Today 1999;20: 278-284.
19. Ertel W, Reichenspurner H, Lerscg C, et al. Cytommunological monitoring in acute rejection and viral. Bacterial or fungal infection following transplantation. Heart Transplant 1985;4: 309-393.
20. Billinghem ME. Diagnosis of cardiac rejection by endomyocardia 155 biopsy. Heart
Transplant 1982;1;25-30.
21. Loertscher R, Forbes BD, Halabi G, et al. Expression of early and activation markers on peripheral blood T lymphocytes does not reliably reflect immune events in transplanted hearts. [J]. Clin Transplant 1994;8(3): 230-238.
22. Cotner T, Williams JM, Christenson L, et al. Simultaneous flow cytometric analysis of human T cell activation antigen expression and DNA content. J EXP Med 1983;157: 461-472.
23. Williams JM, Loertscher R, Cotner T. et al. Dual parameter flow cytometric analysis of DNAcontent, activation antigen expression and T cell subset proliferation in the humanmixed lymphocyte reaction. J Immunol 1984;132: 2330-2337.
24. Windsor NT, Loydk, KS. Young JB, et al. Dynamics of soluble Interleukin-2 receptor levels immediately after heart transplantation. Transplantation 1991;52:78-82
25. Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol Reviews 1987;67: 520-582.
26. Carr MW, Alon R, Springer TA. The c-c chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. [J]. Immunity 1996;4(2): 179-87.
27.李州利,石炳毅,蔡明,等.活化T细胞抗原p140在肾移植患者T淋巴细胞的表达.解放军医学杂志 2002;06.15,27(10):862-864.
28.李州利,石炳毅,蔡明,等.血清sPTA1(CD226)在判别肾移植术后急性排斥反应中的作用.解放军医学杂志 2002;06.15,27(10):865-867.
29.李州利,石炳毅,蔡明,等.PTA1(CD226)与肾脏移植急性排斥反应相关性的研究.肾脏病与透析肾移植杂志 2003;3,11(11):86-89.
30.李州利,石炳毅,蔡明,等.血小板T细胞活化抗原1与移植肾急性排斥反应的相关性.肾脏病与透析肾移植杂志 2003;6,12(03):229-233.
31.李州利,石炳毅,蔡明,等.活化T细胞抗原p140在肝移植患者T淋巴细胞的表达.军医进修学院学报 2006,02.27(1):54-55.
32. Settergren B, Ahlm C, Alexeyev O, et al. Pathogenetic and clinical aspects of the renal involvement in hemorrhagic fever with renal syndrome. Ren Fail 1997;19(1): 1-14.
33. Huang CS, Jin BQ, Wang MX, et al. Hemorrhagic fever with renal syndrome: Relationship between pathogeneses and cellular immunity. J Infectious Disease, 1994;169: 868-870.
34.刘京梅,刘雪松,欧阳为明,等.肾综合征出血热患者 Th1/Th2,T1/T2亚群比例及有关细胞因子变化的研究[J].中华微生物学和免疫学杂志 2002;22(6):610-613.
35. Kagi D, Ledermann B, Burki K, et al. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annual Review of Immunology 1996;14: 207-232.
36. Sabek O, Dorak MT, Kotb M, Gaber AO and Gaber L. Quantitative detection of T-cell activation markers by real-time PCR in renal transplant rejection and correlation with histopathologic evaluation. Transplantation 2002;15:74(5): 701-707.
37. Ohzato H, et al. Serum interleukin-6 levels as an indicator of acute rejection after liver transplantation in cynomologous monkeys. Surg Today 1993;23(6):521
38. Lang T, et al. Production of IL-4 and IL-10 does not lead to immune quiescence in vascularized human organ grafts. Transplantation 1996;62(6): 776
39. Umeshita K, et al. Determination of the presence of interleukin-6 in bile after orthotopic liver transplantation. Its role in the diagnosis of acute rejection. Annsurg 1996;223(2): 204.
40. Roberti I, Lieberman RV, Manzarbeitia C. et al. Evidence that the systematicanalysis of the bile cytology permits monitoring of hepatic allograft rejection. Transplantation 1992;54(3): 471
41. O'Neil S, Hunt J, Filkin J, et al. Obstructive jaundice in rats result in exaggerated hepatic production of of tumor necroosis factor-alpha and systemic and tissue tumor necrosis alpha levels after endootoxin [J]. Surgery, 1997;122: 281-287.
42. David H, R-adhi A, Stephen H, et al.Increased Sensitivity to end toxemia in the bile ductligated cicchotic rat [J]. Heatology 1999;30:1198-1205.
43. Reynolds JV, Murchan P, Redmond HP, et al. Failure of macrophage activation in experimental obstructive jaundice association with bacterial translocation [J]. Br J Surg 1995;82:834-840.
44. Greve JW, Gouma D J, Soeters SB, et al. Suppression of cellular immunity in obstructtive jaundice is caused by endotoxins [J]. Gastroenterology 1990;98: 478-453.
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50.李宁,郎韧,高居忠等.胆汁IL-6水平的检测对早期预测肝移植急性排斥反应的临床意义.北京医学 2001:23 (5):288-291.
51. Tilg H, Nordberg J, Vogel W,et al. Circulatmg serum levels of interleukin-6 and Creactive protein after liver transplantation. Transplantation 1992;54: 142.
52. Umeshita K, Monden M, Tono T, et al. Deteinmation of the presence of interleukm-6 in bile after orthotopic liver transplantation.Its role in the diagnosis of acute rejection. Ann Surg 1996;223: 204.
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57. Shintaku S, Ohdan H, Yamamoto H, et al. Expression of bcl-2 homologue mRNAs in rat liver allograft: Rejection induced cell apoptosis is associated with up-regulation of bax and bcl-xs expression. Transplant Int 1998;11 (Suppl 1): 284-288.
58. Tannapfel A, Kohlhaw K, Ebelt J, et al. Apoptosis and the expression of Fas and Fas ligand (FasL) antigen in rejection and reinfection in liver allograft specimens. Transplantation 1999;67:1079-1083.
2. Meyaa L, Adema G J, Chang C, et al.LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocyte[J].Immunity 1997;7: 283.
3. Xu MI, Zhao RX, Zhao ZJ, et al. Identification and characterization of leukocyteassociated Ig-like receptor-1 as a major anchor Protein of tyrosine phosphatase SHP-1 in hematopoietic cells [J]. J Biol Chem 2000;275: 17440.
4. Sathish JG, Johnson KG, FullerK J, et al. Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells [J]. J Immunol 2001;166: 1763.
5. Van der Vuurst de Vrices AR, Clevers H, Lontenberg T, et al.Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling[J].Eur J Immunol 1999;29:3160.
6. Poggi A, Pellegatta F, Leone BE, et al. Engagement of the leukocyte-associated Ig-like receptor-1 induces programmed cell death and prevents NF-kappaB nuclear translocation in human myeloid leukemias [J].Eur J Immunol 2000;30: 2751.
7. Zocchi MR, Pellegatta F, Pierri I, et al. Leukocyte-associated Ig-like receptor-1 prevents granulocyte-monocyte colony stimulating factor-depedent proliferation and Akt1/PKB alpha activation in primary acute myeloid leukemia cells[J]. Eur J Immunol 2001;31: 3667.
8. Saverino D, Fabbi M, Merlo A, Ravera G, Grossi CE, Ciccone E. Surface density expression of the leukocyte-associated Ig-like receptor-1 is directly related to inhibition of human T-cell functions. Hum Immunol 2002;Jul, 63(7): 534-46.
9.薛江南,欧阳为明,贾卫,等.夹心ELISA检测可溶型LAIR—1方法的建立及其应用的研究.上海免疫学杂志 2003;23(4):268.
10. Butscher WG, Powers C, Olive M, et al. Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/ CREB2. J Biol Chem 1998;273:552 -560.
11. Lebbink RJ, Ruiter T, Verbrugge A, et al.The mouse homologue of the leukocyte- associated Ig-like receptor-1 is an inhibitory receptor that recuits Src homology region 2-containing protein tyrosine phosphatase (SHP)-2, but not SHP-1[J]. J Immunol 2004;172: 5535-5543.
12. Vuurst VAR, Clevers H, Logtenberg T, et al.Leukocyte-associated Ig-like receptor-1 (LAIR-1) is differentially expressed during human B cell differentiation and inhibits B cell receptor-mediated signaling[J].Eur J Immunol 1999;29:3160-3167.
13. De Milito A, Nilsson A, Titanji K, et al. Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004;Mar, 15;103(6): 2180-6.
14. Poggi A, Tomasello E, Ferrero E, et al.p40/LAIR-l regulates the differentiation of peripheral blood precursors to dendritic cells induced by granulocyte-monocyte colony- stimulating factor[J].Eur J Immunol 1998;28:2086-2091.
15. Establishment of an ELISA system for determining soluble LAIR-1 levels in sera of patients with HFRS and kidney transplant. Journal of Immunological Methods 2004;292: 109-117.
16. Bazil V. Physiological enzymatic cleavage of leukocyte membrane molecules. Immunology Today 1995;16:135-140.
17. Hooper NM, Karran EH and Turner AJ. Membrane protein secretase. J Bio Chem 1997;321(pt2): 265-279.
18. Yammamoto S, Higuchi Y, Y oshiyama K, et al. ADAM family proteins in the immune system. Immunology Today 1999;20: 278-284.
19. Ertel W, Reichenspurner H, Lerscg C, et al. Cytommunological monitoring in acute rejection and viral. Bacterial or fungal infection following transplantation. Heart Transplant 1985;4: 309-393.
20. Billinghem ME. Diagnosis of cardiac rejection by endomyocardia 155 biopsy. Heart
Transplant 1982;1;25-30.
21. Loertscher R, Forbes BD, Halabi G, et al. Expression of early and activation markers on peripheral blood T lymphocytes does not reliably reflect immune events in transplanted hearts. [J]. Clin Transplant 1994;8(3): 230-238.
22. Cotner T, Williams JM, Christenson L, et al. Simultaneous flow cytometric analysis of human T cell activation antigen expression and DNA content. J EXP Med 1983;157: 461-472.
23. Williams JM, Loertscher R, Cotner T. et al. Dual parameter flow cytometric analysis of DNAcontent, activation antigen expression and T cell subset proliferation in the humanmixed lymphocyte reaction. J Immunol 1984;132: 2330-2337.
24. Windsor NT, Loydk, KS. Young JB, et al. Dynamics of soluble Interleukin-2 receptor levels immediately after heart transplantation. Transplantation 1991;52:78-82
25. Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol Reviews 1987;67: 520-582.
26. Carr MW, Alon R, Springer TA. The c-c chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. [J]. Immunity 1996;4(2): 179-87.
27.李州利,石炳毅,蔡明,等.活化T细胞抗原p140在肾移植患者T淋巴细胞的表达.解放军医学杂志 2002;06.15,27(10):862-864.
28.李州利,石炳毅,蔡明,等.血清sPTA1(CD226)在判别肾移植术后急性排斥反应中的作用.解放军医学杂志 2002;06.15,27(10):865-867.
29.李州利,石炳毅,蔡明,等.PTA1(CD226)与肾脏移植急性排斥反应相关性的研究.肾脏病与透析肾移植杂志 2003;3,11(11):86-89.
30.李州利,石炳毅,蔡明,等.血小板T细胞活化抗原1与移植肾急性排斥反应的相关性.肾脏病与透析肾移植杂志 2003;6,12(03):229-233.
31.李州利,石炳毅,蔡明,等.活化T细胞抗原p140在肝移植患者T淋巴细胞的表达.军医进修学院学报 2006,02.27(1):54-55.
32. Settergren B, Ahlm C, Alexeyev O, et al. Pathogenetic and clinical aspects of the renal involvement in hemorrhagic fever with renal syndrome. Ren Fail 1997;19(1): 1-14.
33. Huang CS, Jin BQ, Wang MX, et al. Hemorrhagic fever with renal syndrome: Relationship between pathogeneses and cellular immunity. J Infectious Disease, 1994;169: 868-870.
34.刘京梅,刘雪松,欧阳为明,等.肾综合征出血热患者 Th1/Th2,T1/T2亚群比例及有关细胞因子变化的研究[J].中华微生物学和免疫学杂志 2002;22(6):610-613.
35. Kagi D, Ledermann B, Burki K, et al. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annual Review of Immunology 1996;14: 207-232.
36. Sabek O, Dorak MT, Kotb M, Gaber AO and Gaber L. Quantitative detection of T-cell activation markers by real-time PCR in renal transplant rejection and correlation with histopathologic evaluation. Transplantation 2002;15:74(5): 701-707.
37. Ohzato H, et al. Serum interleukin-6 levels as an indicator of acute rejection after liver transplantation in cynomologous monkeys. Surg Today 1993;23(6):521
38. Lang T, et al. Production of IL-4 and IL-10 does not lead to immune quiescence in vascularized human organ grafts. Transplantation 1996;62(6): 776
39. Umeshita K, et al. Determination of the presence of interleukin-6 in bile after orthotopic liver transplantation. Its role in the diagnosis of acute rejection. Annsurg 1996;223(2): 204.
40. Roberti I, Lieberman RV, Manzarbeitia C. et al. Evidence that the systematicanalysis of the bile cytology permits monitoring of hepatic allograft rejection. Transplantation 1992;54(3): 471
41. O'Neil S, Hunt J, Filkin J, et al. Obstructive jaundice in rats result in exaggerated hepatic production of of tumor necroosis factor-alpha and systemic and tissue tumor necrosis alpha levels after endootoxin [J]. Surgery, 1997;122: 281-287.
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