Iranian Journal of Allergy, Asthma and Immunology 2017. 16(6):537-553.

Higher Activities of Hepatic Versus Splenic CD8+ T Cells in Responses to Adoptive T Cell Therapy and Vaccination of B6 Mice with MHC Class-1 Binding Antigen
Mohamed Labib Salem, Randa E. El Naggar, Sabry A. El Naggar, Maysa A. Mobasher, Mohamed H. Mahmoud, Gamal Badr


The liver has unique microenvironment which is known to induce tolerance of cytolytic CD8+ T cells to hepatic and extra hepatic antigens, resulting in persistence of infection of the liver by the hepatitis B and C viruses. However, under some conditions, functional immune responses can be elicited in the liver in particular to show preferential retention of activated CD8+ T cells. It is not clear whether this retention depends on the type of the exogenous immunostimulatory or the endogenous innate immune cells. The T cell receptor (TCR) transgenic OT-1 (CD8+) mouse model was used in which OT-1 cells were harvested from the spleen of the donor and transferred into recipient mice followed by immunization with OVA peptide followed by injection of GM-CSF, CCL21 chemokine, or cytokines (IL-2, IL-12, or IL-15), or the toll-like receptor 3 agonist poly(I:C). Co-administration of any of these immunostimulatory agents relatively augmented the retention of CD8+ T cells with different levels of effects. Compared to spleen, the Ag-specific CD8+ T cells in the liver showed higher activities including expansion, proliferation, apoptosis and memory responses as well as cytolytic function. While depletion of natural killer cells significantly decreased the hepatic retention of the antigen-specific T cells, depletion of Kupffer cells showed opposite effect. Taken together, the antigen reactive T cells in the liver have higher activities than their counterparts in the peripheral tissues such as spleen. These data have important clinical implications for designing immunotherapeutic protocols toward the liver diseases.


CD8+ cyclophosphamide; Kupffer cells; Natural killer cells; Ovalbumin-specific OT-I; OVA; Poly(I:C); T cells; Toll-like receptor; Vaccination

Full Text:



1.         Knudsen ML, Ljungberg K, Kakoulidou M, Kostic L, Hallengard D, Garcia-Arriaza J, Merits A, Esteban M, Liljestrom P: Kinetic and phenotypic analysis of CD8+ T cell responses after priming with alphavirus replicons and homologous or heterologous booster immunizations. Journal of virology 2014, 88(21):12438-12451.

2.         Masopust D, Vezys V, Usherwood EJ, Cauley LS, Olson S, Marzo AL, Ward RL, Woodland DL, Lefrancois L: Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J Immunol 2004, 172(8):4875-4882.

3.         Rai D, Martin MD, Badovinac VP: The longevity of memory CD8 T cell responses after repetitive antigen stimulations. J Immunol 2014, 192(12):5652-5659.

4.         Togher S, Larange A, Schoenberger SP, Feau S: FoxO3 is a negative regulator of primary CD8+ T-cell expansion but not of memory formation. Immunology and cell biology 2015, 93(2):120-125.

5.         Inverso D, Iannacone M: Spatiotemporal dynamics of effector CD8+ T cell responses within the liver. Journal of leukocyte biology 2016, 99(1):51-55.

6.         Wong YC, Tay SS, McCaughan GW, Bowen DG, Bertolino P: Immune outcomes in the liver: Is CD8 T cell fate determined by the environment? J Hepatol 2015, 63(4):1005-1014.

7.         Corradin G, Levitskaya J: Priming of CD8(+) T Cell Responses to Liver Stage Malaria Parasite Antigens. Front Immunol 2014, 5:527.

8.         Shen H, Gonzalez-Juarbe N, Blanchette K, Crimmins G, Bergman MA, Isberg RR, Orihuela CJ, Dube PH: CD8(+) T cells specific to a single Yersinia pseudotuberculosis epitope restrict bacterial replication in the liver but fail to provide sterilizing immunity. Infect Genet Evol 2016, 43:289-296.

9.         Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P: The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 2004, 114(5):701-712.

10.       Mehal WZ, Juedes AE, Crispe IN: Selective retention of activated CD8+ T cells by the normal liver. J Immunol 1999, 163(6):3202-3210.

11.       Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B: Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol 2001, 166(9):5430-5438.

12.       Bertolino P, Heath WR, Hardy CL, Morahan G, Miller JF: Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver. European journal of immunology 1995, 25(7):1932-1942.

13.       Bertolino P, Trescol-Biemont MC, Rabourdin-Combe C: Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. European journal of immunology 1998, 28(1):221-236.

14.      von Oppen N, Schurich A, Hegenbarth S, Stabenow D, Tolba R, Weiskirchen R, Geerts A, Kolanus W, Knolle P, Diehl L: Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization. Hepatology 2009, 49(5):1664-1672.

15.       Lukens JR, Dolina JS, Kim TS, Tacke RS, Hahn YS: Liver is able to activate naive CD8+ T cells with dysfunctional anti-viral activity in the murine system. PloS one 2009, 4(10):e7619.

16.       Kaczmarek J, Homsi Y, van Uum J, Metzger C, Knolle PA, Kolanus W, Lang T, Diehl L: Liver sinusoidal endothelial cell-mediated CD8 T cell priming depends on co-inhibitory signal integration over time. PloS one 2014, 9(6):e99574.

17.       Hochst B, Schildberg FA, Bottcher J, Metzger C, Huss S, Turler A, Overhaus M, Knoblich A, Schneider B, Pantelis D et al: Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice. Hepatology 2012, 56(5):1924-1933.

18.       Schildberg FA, Hegenbarth SI, Schumak B, Scholz K, Limmer A, Knolle PA: Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. European journal of immunology 2008, 38(4):957-967.

19.       Dolina JS, Braciale TJ, Hahn YS: Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice. Hepatology 2014, 59(4):1351-1365.

20.       Holz LE, Benseler V, Vo M, McGuffog C, Van Rooijen N, McCaughan GW, Bowen DG, Bertolino P: Naive CD8 T cell activation by liver bone marrow-derived cells leads to a "neglected" IL-2low Bimhigh phenotype, poor CTL function and cell death. J Hepatol 2012, 57(4):830-836.

21.       Spahn J, Pierce RH, Crispe IN: Ineffective CD8(+) T-cell immunity to adeno-associated virus can result in prolonged liver injury and fibrogenesis. Am J Pathol 2011, 179(5):2370-2381.

22.       Bochtler P, Riedl P, Gomez I, Schirmbeck R, Reimann J: Local accumulation and activation of regulatory Foxp3+ CD4 T(R) cells accompanies the appearance of activated CD8 T cells in the liver. Hepatology 2008, 48(6):1954-1963.

23.       Kuniyasu Y, Marfani SM, Inayat IB, Sheikh SZ, Mehal WZ: Kupffer cells required for high affinity peptide-induced deletion, not retention, of activated CD8+ T cells by mouse liver. Hepatology 2004, 39(4):1017-1027.

24.       Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H: The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses. Immunological reviews 2000, 174:35-46.

25.       Seki S, Nakashima H, Nakashima M, Kinoshita M: Antitumor immunity produced by the liver Kupffer cells, NK cells, NKT cells, and CD8 CD122 T cells. Clinical & developmental immunology 2011, 2011:868345.

26.       Chabot S, Fakhfakh A, Beland K, Lamarre A, Oldstone MB, Alvarez F, Djilali-Saiah I: Mouse liver-specific CD8(+) T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes. Journal of autoimmunity 2013, 42:19-28.

27.       Fernandez-Ruiz D, Ng WY, Holz LE, Ma JZ, Zaid A, Wong YC, Lau LS, Mollard V, Cozijnsen A, Collins N et al: Liver-Resident Memory CD8+ T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection. Immunity 2016, 45(4):889-902.

28.       Lang Kuhs KA, Toporovski R, Ginsberg AA, Olsen AL, Shedlock DJ, Morrow MP, Yan J, Wells RG, Weiner DB: Peripheral immunization induces functional intrahepatic hepatitis C specific immunity following selective retention of vaccine-specific CD8 T cells by the liver. Hum Vaccin 2011, 7(12):1326-1335.

29.       Knolle PA: Involvement of the liver in the induction of CD8 T cell tolerance towards oral antigen. Z Gastroenterol 2006, 44(1):51-56.

30.       Belardelli F, Ferrantini M: Cytokines as a link between innate and adaptive antitumor immunity. Trends in immunology 2002, 23(4):201-208.

31.       Liew FY: The role of innate cytokines in inflammatory response. Immunology letters 2003, 85(2):131-134.

32.       Curtsinger JM, Schmidt CS, Mondino A, Lins DC, Kedl RM, Jenkins MK, Mescher MF: Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol 1999, 162(6):3256-3262.

33.       Curtsinger JM, Johnson CM, Mescher MF: CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J Immunol 2003, 171(10):5165-5171.

34.       Curtsinger JM, Valenzuela JO, Agarwal P, Lins D, Mescher MF: Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 2005, 174(8):4465-4469.

35.      Valenzuela JO, Hammerbeck CD, Mescher MF: Cutting edge: Bcl-3 up-regulation by signal 3 cytokine (IL-12) prolongs survival of antigen-activated CD8 T cells. J Immunol 2005, 174(2):600-604.

36.       Salem ML, Kadima AN, Zhou Y, Nguyen CL, Rubinstein MP, Demcheva M, Vournakis JN, Cole DJ, Gillanders WE: Paracrine release of IL-12 stimulates IFN-gamma production and dramatically enhances the antigen-specific T cell response after vaccination with a novel peptide-based cancer vaccine. J Immunol 2004, 172(9):5159-5167.

37.       Salem ML, Kadima AN, Cole DJ, Gillanders WE: Defining the Antigen-Specific T-Cell Response to Vaccination and Poly(I:C)/TLR3 Signaling: Evidence of Enhanced Primary and Memory CD8 T-Cell Responses and Antitumor Immunity. J Immunother 2005, 28(3):220-228.

38.       Salem ML, El-Naggar SA, Kadima A, Gillanders WE, Cole DJ: The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 2006, 24(24):5119-5132.

39.       Rubinstein MP, Kadima AN, Salem ML, Nguyen CL, Gillanders WE, Cole DJ: Systemic administration of IL-15 augments the antigen-specific primary CD8+ T cell response following vaccination with peptide-pulsed dendritic cells. J Immunol 2002, 169(9):4928-4935.

40.       Nguyen CL, Salem ML, Rubinstein MP, Demcheva M, Vournakis J, Cole DJ, Gillanders WE: Mechanisms of enhanced antigen-specific T cell response following vaccination with a novel peptide-based cancer vaccine and systemic interleukin-2 (IL-2). Vaccine 2003, In Press.

41.       Caux C, Ait-Yahia S, Chemin K, de Bouteiller O, Dieu-Nosjean MC, Homey B, Massacrier C, Vanbervliet B, Zlotnik A, Vicari A: Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. Springer Semin Immunopathol 2000, 22(4):345-369.

42.       Liao Y, Geng P, Tian Y, Miao H, Liang H, Zeng R, Ni B, Ruan Z: Marked anti-tumor effects of CD8(+)CD62L(+) T cells from melanoma-bearing mice. Immunol Invest 2015, 44(2):147-163.

43.       Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, Sprent J: Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proceedings of the National Academy of Sciences of the United States of America 2006, 103(24):9166-9171.

44.       Diaz-Montero CM, El Naggar S, Al Khami A, El Naggar R, Montero AJ, Cole DJ, Salem ML: Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8+CD62Lhi cells and results in superior anti-tumor activity in a tolerogenic murine model. Cancer immunology, immunotherapy : CII 2008, 57(4):563-572.

45.       Salem ML, Attia WY, Al-Bolkiny YE, Al-Sharkawi IM, Demcheva M, Vournakis J: Using poly-N-acetyl glucosamine gel matrix to deliver IL-12 with anti-schistosomasis vaccination. J Infect Dev Ctries 2010, 4(5):318-328.

46.       Diaz-Montero CM, Naga O, Zidan AA, Salem ML, Pallin M, Parmigiani A, Walker G, Wieder E, Komanduri K, Cole DJ et al: Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory. Am J Cancer Res 2011, 1(7):882-896.

47.      Rubinstein MP, Cloud CA, Garrett TE, Moore CJ, Schwartz KM, Johnson CB, Craig DH, Salem ML, Paulos CM, Cole DJ: Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 2012, 214(4):700-707; discussion 707-708.

48.       Rubinstein MP, Salem ML, Doedens AL, Moore CJ, Chiuzan C, Rivell GL, Cole DJ, Goldrath AW: G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses. J Hematol Oncol 2013, 6:75.

49.      Diaz-Montero CM, Zidan AA, Pallin MF, Anagnostopoulos V, Salem ML, Wieder E, Komanduri K, Montero AJ, Lichtenheld MG: Understanding the biology of ex vivo-expanded CD8 T cells for adoptive cell therapy: role of CD62L. Immunol Res 2013, 57(1-3):23-33.

50.       Salem ML, Shoukry NM, Zidan AA, Vournakis J: Immunomodulatory effects of IL-12 released from poly-N-acetyl glucosamine gel matrix during schistosomiasis infection. Cytotechnology 2014, 66(4):667-675.

51.       Rubinstein MP, Su EW, Suriano S, Cloud CA, Andrijauskaite K, Kesarwani P, Schwartz KM, Williams KM, Johnson CB, Li M et al: Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells. Cancer immunology, immunotherapy : CII 2015, 64(5):539-549.

52.       Salem ML, Nassef M, Abdel Salam SG, Zidan A, Mahmoud MH, Badr G, Rubinstein M, Cole D: Effect of administration timing of postchemotherapy granulocyte colony-stimulating factor on host-immune cell recovery and CD8+ T-cell response. J Immunotoxicol 2016:1-9.

53.       Salem ML, Gillanders WE, Kadima AN, El-Naggar S, Rubinstein MP, Demcheva M, Vournakis JN, Cole DJ: Review: novel nonviral delivery approaches for interleukin-12 protein and gene systems: curbing toxicity and enhancing adjuvant activity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2006, 26(9):593-608.

54.       Salem ML, Kadima AN, El-Naggar SA, Rubinstein MP, Chen Y, Gillanders WE, Cole DJ: Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J Immunother (1997) 2007, 30(1):40-53.

55.       Salem ML, Diaz-Montero CM, El-Naggar SA, Chen Y, Moussa O, Cole DJ: The TLR3 agonist poly(I:C) targets CD8+ T cells and augments their antigen-specific responses upon their adoptive transfer into naive recipient mice. Vaccine 2009, 27(4):549-557.

56.       Salem ML, Diaz-Montero CM, Al-Khami AA, El-Naggar SA, Naga O, Montero AJ, Khafagy A, Cole DJ: Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol 2009, 182(4):2030-2040.

57.       Salem ML, Al-Khami AA, El-Naggar SA, Diaz-Montero CM, Chen Y, Cole DJ: Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. J Immunol 2010, 184(4):1737-1747.

58.       Salem ML, Cole DJ: Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer immunology, immunotherapy : CII 2010, 59(3):341-353.

59.       Salem ML, Demcheva M, Gillanders WE, Cole DJ, Vournakis JN: Poly-N-acetyl glucosamine gel matrix as a non-viral delivery vector for DNA-based vaccination. Anticancer research 2010, 30(10):3889-3894.

60.       Salem ML, El-Demellawy M, El-Azm AR: The potential use of Toll-like receptor agonists to restore the dysfunctional immunity induced by hepatitis C virus. Cellular immunology 2010, 262(2):96-104.

61.       Salem ML, El-Naggar SA, Cole DJ: Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cellular immunology 2010, 261(2):134-143.

62.       Salem ML: Triggering of toll-like receptor signaling pathways in T cells contributes to the anti-tumor efficacy of T cell responses. Immunology letters 2011, 137(1-2):9-14.

63.       Salem ML, Alenzi FQ, Attia WY: Thymoquinone, the active ingredient of Nigella sativa seeds, enhances survival and activity of antigen-specific CD8-positive T cells in vitro. Br J Biomed Sci 2011, 68(3):131-137.

64.       Alenzi FQ, Alenazi FA, Al-Kaabi Y, Salem ML: The use of growth factors to modulate the activities of antigen-specific CD8+ T cells in vitro. J Med Life 2011, 4(4):399-406.

65.       Fox BA, Schendel DJ, Butterfield LH, Aamdal S, Allison JP, Ascierto PA, Atkins MB, Bartunkova J, Bergmann L, Berinstein N et al: Defining the critical hurdles in cancer immunotherapy. J Transl Med 2011, 9:214.

66.       Salem ML, Al-Khami AA, El-Nagaar SA, Zidan AA, Al-Sharkawi IM, Marcela Diaz-Montero C, Cole DJ: Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide. Cellular immunology 2012, 276(1-2):67-74.

67.       Salem ML: The use of dendritic cells for peptide-based vaccination in cancer immunotherapy. Methods Mol Biol 2014, 1139:479-503.

68.       Salem ML, Hammad SM, El-shanshory MR, Attia MA, Zidan A-AA: Immunostimulatory Effects of Triggering TLR3 Signaling Pathway — Implication for Cancer Immunotherapy; 2014.

69.       Andrijauskaite K, Suriano S, Cloud CA, Li M, Kesarwani P, Stefanik LS, Moxley KM, Salem ML, Garrett-Mayer E, Paulos CM et al: IL-12 conditioning improves retrovirally mediated transduction efficiency of CD8+ T cells. Cancer Gene Ther 2015, 22(7):360-367.

70.       Salem ML, Attia ZI, Galal SM: Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model. J Adv Res 2016, 7(2):243-253.

71.       Salem ML, Shoukry NM, Teleb WK, Abdel-Daim MM, Abdel-Rahman MA: In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model. Springerplus 2016, 5:570.

72.       Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP: The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunological reviews 2000, 174:47-62.

73.       Krueger PD, Kim TS, Sung SS, Braciale TJ, Hahn YS: Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol 2015, 194(7):3213-3222.

74.       Xia S, Guo Z, Yao Y, Xu X, Yi H, Xia D, Cao X: Liver stroma enhances activation of TLR3-triggered NK cells through fibronectin. Mol Immunol 2008, 45(10):2831-2838.

75.       Riise RE, Bernson E, Aurelius J, Martner A, Pesce S, Della Chiesa M, Marcenaro E, Bylund J, Hellstrand K, Moretta L et al: TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses. J Immunol 2015, 195(3):1121-1128.

76.       Adib-Conquy M, Scott-Algara D, Cavaillon JM, Souza-Fonseca-Guimaraes F: TLR-mediated activation of NK cells and their role in bacterial/viral immune responses in mammals. Immunology and cell biology 2014, 92(3):256-262.

77.       Emoto M, Miyamoto M, Namba K, Schmits R, Van Rooijen N, Kita E, Kaufmann SH: Participation of leukocyte function-associated antigen-1 and NK cells in the homing of thymic CD8+NKT cells to the liver. European journal of immunology 2000, 30(10):3049-3056.

78.       Wu K, Kryczek I, Chen L, Zou W, Welling TH: Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer research 2009, 69(20):8067-8075.

79.       Dolina JS, Sung SS, Novobrantseva TI, Nguyen TM, Hahn YS: Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity. Mol Ther Nucleic Acids 2013, 2:e72.

80.       Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS: TLR-dependent cross talk between human Kupffer cells and NK cells. The Journal of experimental medicine 2008, 205(1):233-244.

81.       Ju C, McCoy JP, Chung CJ, Graf ML, Pohl LR: Tolerogenic role of Kupffer cells in allergic reactions. Chemical research in toxicology 2003, 16(12):1514-1519.

82.       Oikawa T, Takahashi H, Ishikawa T, Hokari A, Otsuki N, Azuma M, Zeniya M, Tajiri H: Intrahepatic expression of the co-stimulatory molecules programmed death-1, and its ligands in autoimmune liver disease. Pathol Int 2007, 57(8):485-492.

83.       Verhoven B, Schlegel RA, Williamson P: Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. The Journal of experimental medicine 1995, 182(5):1597-1601.

84.       Ruzittu M, Carla EC, Montinari MR, Maietta G, Dini L: Modulation of cell surface expression of liver carbohydrate receptors during in vivo induction of apoptosis with lead nitrate. Cell Tissue Res 1999, 298(1):105-112.

85.       Dini L, Giudetti AM, Ruzittu M, Gnoni GV, Zara V: Citrate carrier and lipogenic enzyme activities in lead nitrate-induced proliferative and apoptotic phase in rat liver. Biochem Mol Biol Int 1999, 47(4):607-614.

86.       Dini L, Ruzittu M, Carla EC, Falasca L: Relationship between cellular shape and receptor-mediated endocytosis: an ultrastructural and morphometric study in rat Kupffer cells. Liver 1998, 18(2):99-109.

87.       Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG: Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease. J Clin Invest 2002, 109(10):1335-1344.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.