• 昆明醫(yī)科大學(xué)第二附屬醫(yī)院肝膽胰一病區(qū)（云南昆明650101）;

目的 　了解Toll樣受體（TLRs）信號(hào)傳導(dǎo)通路及其在器官移植中的作用的研究進(jìn)展。
方法 　通過文獻(xiàn)檢索并總結(jié)TLRs及其配體結(jié)構(gòu)、功能的特點(diǎn)，就近年來TLRs信號(hào)傳導(dǎo)通路在動(dòng)物實(shí)驗(yàn)和臨床器官移植中的作用的研究進(jìn)展進(jìn)行綜述。
結(jié)果 　TLRs在器官移植中發(fā)揮著重要作用，TLRs的活化可激活特異性免疫系統(tǒng)，使移植物發(fā)生缺血再灌注損傷、急性排斥反應(yīng)和慢性排斥反應(yīng)，同時(shí)也可通過TLRs誘導(dǎo)免疫耐受。早期治療措施的干預(yù)可減少器官移植中移植物因缺血再灌注損傷所致的TLRs激活，從而提高移植物存活率；同時(shí)，針對(duì)TLRs及其介導(dǎo)的信號(hào)傳導(dǎo)通路的相關(guān)免疫抑制靶點(diǎn)研發(fā)出的高效免疫抑制藥物可減輕器官移植后缺血再灌注損傷和免疫排斥反應(yīng)。
結(jié)論 　TLRs信號(hào)傳導(dǎo)通路在缺血再灌注損傷、免疫排斥及免疫調(diào)節(jié)中起著重要作用。

引用本文： 張黎,胡明道,陳鵬. Toll樣受體信號(hào)傳導(dǎo)通路及其在器官移植中作用的研究進(jìn)展△. 中國(guó)普外基礎(chǔ)與臨床雜志, 2012, 19(11): 1243-1248. doi: 復(fù)制

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2. Takeda K， Kaisho T， Akira S. Toll-like receptors[J]. Annu Rev Immunol， 2003， 21：335-376.
3. Asprodites N， Zheng L， Geng D， et al. Engagement of toll-like receptor-2 on cytotoxic t-lymphocytes occurs in vivo and augments antitumor activity[J]. FASEB J， 2008， 22(10)：3628-3637.
4. Lorenz E. TLR2 and TLR4 expression during bacterial infections[J]. Curr Pharm Des， 2006， 12(32)：4185-4193.
5. Boehme KW， Guerrero M， Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells[J]. J Immunol， 2006， 177(10)：7094-7102.
6. Krasowska-Zoladek A， Banaszewska M， Kraszpulski M， et al. Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation[J]. J Neurosci Res， 2007， 85(1)：205-212.
7. Tabeta K， Georgel P， Janssen E， et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection[J]. Proc Natl Acad Sci USA， 2004， 101(10)：3516-3521.
8. Arbour NC， Lorenz E， Schutte BC， et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. Nat Genet， 2000， 25(2)：187-191.
9. Miyamoto Y， Iimura M， Kaper JB， et al. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic escherichia coli signa-ling of human colon epithelium in vivo[J]. Cell Microbiol， 2006， 8(5)：869-879.
10. Guan Y， Ranoa DR， Jiang S， et al. Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling[J]. J Immunol， 2010， 184(9)：5094-5103.
11. Lauw FN， Caffrey DR， Golenbock DT. Of mice and man：TLR11 (finally) finds profilin[J]. Trends Immunol， 2005， 26(10)：509-511.
12. Rubartelli A， Lotze MT. Inside， outside， upside down：damage-associated molecular-pattern molecules (DAMPs) and redox[J]. Trends Immunol， 2007， 28(10)：429-436.
13. Shirali AC， Goldstein DR. Activation of the innate immune system by the endogenous ligand hyaluronan[J]. Curr Opin Organ Transplant， 2008， 13(1)：20-25.
14. Tesar BM， Jiang D， Liang J， et al. The role of hyaluronan degradation products as innate alloimmune agonists[J]. Am J Transplant， 2006， 6(11)：2622-2635.
15. Pockley AG. Heat shock proteins， anti-heat shock protein reactivity and allograft rejection[J]. Transplantation， 2001， 71(11)：1503-1507.
16. Alegre ML， Goldstein DR， Chong AS. Toll-like receptor signaling in transplantation[J]. Curr Opin Organ Transplant， 2008， 13(4)：358-365.
17. Zhai Y， Qiao B， Shen XD， et al. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury[J]. Transplantation， 2008， 85(7)：1016-1022.
18. -dependent transplant rejection[J]. J Immunol， 2009， 182 (10)：6217-6225.
19. Beg AA. Endogenous ligands of Toll-like receptors：implications for regulating inflammatory and immune responses[J]. Trends Immunol， 2002， 23(11)：509-512.
20. O’Neill LA， Bowie AG. The family of five：TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol， 2007， 7(5)：353-364.
21. Choi YJ， Im E， Chung HK， et al. TRIF mediates Toll-likereceptor 5-induced signaling in intestinal epithelial cells[J]. J Biol Chem， 2010， 285(48)：37570-37578.
22. Choi YJ， Im E， Pothoulakis C， et al. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5[J]. J Biol Chem， 2010， 285(28)：21382-21390.
23. Liberati NT， Fitzgerald KA， Kim DH， et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response[J]. Proc Natl Acad Sci USA， 2004， 101(17)：6593-6598.
24. Wald D， Qin J， Zhao Z， et al. SIGIRR， a negative regulator of Toll-like receptor-interleukin 1 receptor signaling[J]. Nat Immunol， 2003， 4(9)：920-927.
25. 朱旭輝， 楊明金. CMRF35樣分子對(duì)Toll樣受體信號(hào)通路的影響及其機(jī)制的研究進(jìn)展[J]. 中國(guó)腫瘤生物治療雜志， 2011， 18(1)：101-104.
26. Goldstein DR， Tesar BM， Akira S， et al. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection[J]. J Clin Invest， 2003， 111(10)：1571-1578.
27. Tesar BM， Zhang J， Li Q， et al. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88， a toll-like receptor signal adaptor protein[J]. Am J Transplant， 2004， 4(9)：1429-1439.
28. McKay D， Shigeoka A， Rubinstein M， et al. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection[J]. Eur J Immunol， 2006， 36(8)：1994-2002.
29. Wang T， Chen L， Ahmed E， et al. Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes[J]. J Immunol， 2008， 180(9)：5991-5999.
30. Chen L， Wang T， Zhou P， et al. TLR engagement prevents transplantation tolerance[J]. Am J Transplant， 2006， 6(10)：2282-2291.
31. Shen H， Goldstein DR. IL-6 and TNF-α synergistically inhibitallograft acceptance[J]. J Am Soc Nephrol， 2009， 20(5)：1032-1040.
32. Bettelli E， Oukka M， Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity[J]. Nat Immunol， 2007， 8(4)：345-350.
33. Porrett PM， Yuan X， Larosa DF， et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands[J]. J Immunol， 2008， 181(3)：1692-1699.
34. Chen L， Ahmed E， Wang T， et al. TLR signals promote IL-6/IL-.
35. Smirnova I， Hamblin MT， McBride C， et al. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans[J]. Genetics， 2001， 158(4)：1657-1664.
36. Palmer SM， Burch LH， Davis RD， et al. The role of innateimmunity in acute allograft rejection after lung transplantation[J]. Am J Respir Crit Care Med， 2003， 168(6)：628-632.
37. Ducloux D， Deschamps M， Yannaraki M， et al. Relevance of toll-like receptor-4 polymorphisms in renal transplantation[J]. Kidney Int， 2005， 67(6)：2454-2461.
38. Krüger B， Krick S， Dhillon N， et al. Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation[J]. Proc Natl Acad Sci USA， 2009， 106(9)：3390-3395.
39. Methe H， Zimmer E， Grimm C， et al. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation[J]. Transplantation， 2004， 78(9)：1324-1331.
40. McDaniel DO， Zhou X， Moore CK， et al. Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1[J]. Transplant Proc， 2010， 42(10)：4235-4237.
41. Citores MJ， Baños I， Noblejas A， et al. Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis[J]. Transplant Proc， 2011， 43(6)：2224-2226.
42. Ge X， Uzunel M， Ericzon BG， et al. Biliary epithelial cell antibodies induce expression of toll-like receptors 2 and 3：a mechanism for post-liver transplantation cholangitis?[J]. Liver Transpl， 2005， 11(8)：911-921.
  1. 1. Medzhitov R， Preston-Hurlburt P， Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J]. Nature， 1997， 388(6640)：394-397.
  2. 2. Takeda K， Kaisho T， Akira S. Toll-like receptors[J]. Annu Rev Immunol， 2003， 21：335-376.
  3. 3. Asprodites N， Zheng L， Geng D， et al. Engagement of toll-like receptor-2 on cytotoxic t-lymphocytes occurs in vivo and augments antitumor activity[J]. FASEB J， 2008， 22(10)：3628-3637.
  4. 4. Lorenz E. TLR2 and TLR4 expression during bacterial infections[J]. Curr Pharm Des， 2006， 12(32)：4185-4193.
  5. 5. Boehme KW， Guerrero M， Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells[J]. J Immunol， 2006， 177(10)：7094-7102.
  6. 6. Krasowska-Zoladek A， Banaszewska M， Kraszpulski M， et al. Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation[J]. J Neurosci Res， 2007， 85(1)：205-212.
  7. 7. Tabeta K， Georgel P， Janssen E， et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection[J]. Proc Natl Acad Sci USA， 2004， 101(10)：3516-3521.
  8. 8. Arbour NC， Lorenz E， Schutte BC， et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. Nat Genet， 2000， 25(2)：187-191.
  9. 9. Miyamoto Y， Iimura M， Kaper JB， et al. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic escherichia coli signa-ling of human colon epithelium in vivo[J]. Cell Microbiol， 2006， 8(5)：869-879.
  10. 10. Guan Y， Ranoa DR， Jiang S， et al. Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling[J]. J Immunol， 2010， 184(9)：5094-5103.
  11. 11. Lauw FN， Caffrey DR， Golenbock DT. Of mice and man：TLR11 (finally) finds profilin[J]. Trends Immunol， 2005， 26(10)：509-511.
  12. 12. Rubartelli A， Lotze MT. Inside， outside， upside down：damage-associated molecular-pattern molecules (DAMPs) and redox[J]. Trends Immunol， 2007， 28(10)：429-436.
  13. 13. Shirali AC， Goldstein DR. Activation of the innate immune system by the endogenous ligand hyaluronan[J]. Curr Opin Organ Transplant， 2008， 13(1)：20-25.
  14. 14. Tesar BM， Jiang D， Liang J， et al. The role of hyaluronan degradation products as innate alloimmune agonists[J]. Am J Transplant， 2006， 6(11)：2622-2635.
  15. 15. Pockley AG. Heat shock proteins， anti-heat shock protein reactivity and allograft rejection[J]. Transplantation， 2001， 71(11)：1503-1507.
  16. 16. Alegre ML， Goldstein DR， Chong AS. Toll-like receptor signaling in transplantation[J]. Curr Opin Organ Transplant， 2008， 13(4)：358-365.
  17. 17. Zhai Y， Qiao B， Shen XD， et al. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury[J]. Transplantation， 2008， 85(7)：1016-1022.
  18. 18. -dependent transplant rejection[J]. J Immunol， 2009， 182 (10)：6217-6225.
  19. 19. Beg AA. Endogenous ligands of Toll-like receptors：implications for regulating inflammatory and immune responses[J]. Trends Immunol， 2002， 23(11)：509-512.
  20. 20. O’Neill LA， Bowie AG. The family of five：TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol， 2007， 7(5)：353-364.
  21. 21. Choi YJ， Im E， Chung HK， et al. TRIF mediates Toll-likereceptor 5-induced signaling in intestinal epithelial cells[J]. J Biol Chem， 2010， 285(48)：37570-37578.
  22. 22. Choi YJ， Im E， Pothoulakis C， et al. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5[J]. J Biol Chem， 2010， 285(28)：21382-21390.
  23. 23. Liberati NT， Fitzgerald KA， Kim DH， et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response[J]. Proc Natl Acad Sci USA， 2004， 101(17)：6593-6598.
  24. 24. Wald D， Qin J， Zhao Z， et al. SIGIRR， a negative regulator of Toll-like receptor-interleukin 1 receptor signaling[J]. Nat Immunol， 2003， 4(9)：920-927.
  25. 25. 朱旭輝， 楊明金. CMRF35樣分子對(duì)Toll樣受體信號(hào)通路的影響及其機(jī)制的研究進(jìn)展[J]. 中國(guó)腫瘤生物治療雜志， 2011， 18(1)：101-104.
  26. 26. Goldstein DR， Tesar BM， Akira S， et al. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection[J]. J Clin Invest， 2003， 111(10)：1571-1578.
  27. 27. Tesar BM， Zhang J， Li Q， et al. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88， a toll-like receptor signal adaptor protein[J]. Am J Transplant， 2004， 4(9)：1429-1439.
  28. 28. McKay D， Shigeoka A， Rubinstein M， et al. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection[J]. Eur J Immunol， 2006， 36(8)：1994-2002.
  29. 29. Wang T， Chen L， Ahmed E， et al. Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes[J]. J Immunol， 2008， 180(9)：5991-5999.
  30. 30. Chen L， Wang T， Zhou P， et al. TLR engagement prevents transplantation tolerance[J]. Am J Transplant， 2006， 6(10)：2282-2291.
  31. 31. Shen H， Goldstein DR. IL-6 and TNF-α synergistically inhibitallograft acceptance[J]. J Am Soc Nephrol， 2009， 20(5)：1032-1040.
  32. 32. Bettelli E， Oukka M， Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity[J]. Nat Immunol， 2007， 8(4)：345-350.
  33. 33. Porrett PM， Yuan X， Larosa DF， et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands[J]. J Immunol， 2008， 181(3)：1692-1699.
  34. 34. Chen L， Ahmed E， Wang T， et al. TLR signals promote IL-6/IL-.
  35. 35. Smirnova I， Hamblin MT， McBride C， et al. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans[J]. Genetics， 2001， 158(4)：1657-1664.
  36. 36. Palmer SM， Burch LH， Davis RD， et al. The role of innateimmunity in acute allograft rejection after lung transplantation[J]. Am J Respir Crit Care Med， 2003， 168(6)：628-632.
  37. 37. Ducloux D， Deschamps M， Yannaraki M， et al. Relevance of toll-like receptor-4 polymorphisms in renal transplantation[J]. Kidney Int， 2005， 67(6)：2454-2461.
  38. 38. Krüger B， Krick S， Dhillon N， et al. Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation[J]. Proc Natl Acad Sci USA， 2009， 106(9)：3390-3395.
  39. 39. Methe H， Zimmer E， Grimm C， et al. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation[J]. Transplantation， 2004， 78(9)：1324-1331.
  40. 40. McDaniel DO， Zhou X， Moore CK， et al. Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1[J]. Transplant Proc， 2010， 42(10)：4235-4237.
  41. 41. Citores MJ， Baños I， Noblejas A， et al. Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis[J]. Transplant Proc， 2011， 43(6)：2224-2226.
  42. 42. Ge X， Uzunel M， Ericzon BG， et al. Biliary epithelial cell antibodies induce expression of toll-like receptors 2 and 3：a mechanism for post-liver transplantation cholangitis?[J]. Liver Transpl， 2005， 11(8)：911-921.