The aim of this study was to investigate the ability of portovenously administered donor antigens to induce immune hyporesponsiveness. Lewis (LEW, RT-1l) rats received Brown Norway (BN, RT-1n) rat donor splenocytes, via either the portal vein (PV group) or the peripheral vein (IV group). The immune responses of LEW rats, treated with either donor BN or third party Wistar King A (WKA, RT-1k) splenocytes were established by the persistence of donor dendritic cells (DCs) in the host liver measured using fluorescence microscopy and flow cytometry and by the mixed lymphocyte reaction (MLR). The effect of intravenous gadolinium chloride (GDCl3) on the blockade of Kupffer cell function prior to portovenous administration of splenocytes was also assessed. The MLR response was strongly inhibited in a BN-restricted manner after portovenous administration of donor BN splenocytes, but not by venous nor by portovenous administration of WKA splenocytes. Immunosuppression was blocked by pretreatment with GDCl3. The percentage of donor DCs in hepatic non-parenchymal cells (NPCs) was significantly higher in the PV group compared with the IV group. Treatment with GDCl3 decreased the percentage of donor DCs. In addition, cytotoxic T lymphocyte antigen 4 (CTLA4/CD152), which may function as an immune attenuator, was strongly stained, and B7 was weakly stained in recipient liver in the PV group compared with the IV group. These results suggest that both donor DCs and recipient Kupffer cells (self DCs) are involved in the induction of immune hyporesponsiveness by donor cells. This occurs via portovenous administration, in which a signal of the CTLA4–B7 pathway played an important part in inhibiting the interaction of CD28 and its B7 ligands.
SulzbergerMB: Arsphename hypersensitiveness in guinea-pigs. Experiments demonstrating the role of skin, both as originator and as site of hypersensitiveness. Arch Dermatol Syphilol1930; 22: 839
2.
ChaseMW: Inhibition of experimental drug allergy by prior feeding of the sensitizing agents. Proc Soc Exp Biol Med1946; 61: 257–259
3.
YoshimuraNMatsuiSHamashimaTLeeCJOhsakaYOkaT: The effects of perioperative portal venous inoculation with donor lymphocytes on renal allograft survival in the rat. I. Specific prolongation of donor grafts and suppressor factor in the serum. Transplantation1990; 49: 167–171
4.
FujiwaraHQianJHSatohSKokundoSIkeyamiRHamaokaR: Studies on the induction of tolerance to alloantigen. II. The generation of serum factors able to transfer alloantigen-specific tolerance for delayed type hypersensitivity by portal venous inoculation with allogeneic cells. J Immunol1986; 136: 2763–2768
5.
KenickSLisbonaRMarghescoD: Prolonged cardiac allograft survival following portal venous inoculation of allogeneic cells: immunologically specific entrapment of allogeneic cells within the liver. Transplant Proc1987; 19: 3057–3060
6.
RaoVKBurrisDEGruelSMSollingerHWBurlinghamWJ: Evidence that donor spleen cells administered through the portal vein prolong the survival of cardiac allografts in rats. Transplantation1988; 45: 1145–1146
7.
NakanoYMondenMValdiviaLAGotohMTonoTMoriT: Permanent acceptance of liver allografts by intraportal injection of donor spleen cells in rats. Surgery1992; 111: 668–676
8.
TriggerDRCynamonMHWrightR: Studies on hepatic uptake of antigen. I. Comparison of inferior vena cava and portal vein route of immunization. Immunology1973; 25: 941–950
9.
CalleryMPManginoMJFlyeMW: Arginine-specific suppression of mixed lymphocyte culture reactivity by Kupffer cells — a basis of portal venous tolerance. Transplantation1991; 51: 1076–1080
10.
GorczynskiRMWojcikD: A role for nonspecific (cyclosporin A) or specific (monoclonal antibodies to ICAM-1, LFA-1 and IL-10) immunomodulation in the prolongation of skin allografts after antigen-specific pre-transplant immunization or transfusion. J Immunol1994; 152: 2011–2019
11.
IshidoNMatsuokaJMatsunoTNakagawaKTanakaN: Induction of donor specific hyporesponsiveness and prolongation of cardiac allograft survival by jejunal administration of donor splenocytes. Transplantation1999; 68: 1377–1382
12.
UdaMFujiwaraTKusakaSMatsunoTTanakaNOritaK: Donor specific inhibitory factor induced by portal venous inoculation with ultraviolet-B irradiated spleen cells in non-human primates. Transplant Proc1994; 26: 1848–1850
13.
HusztikELazarGParduczA: Electron microscopic study of Kupffer cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol1980; 61: 624–630
14.
KrenskyAMWeissACrabtreeGDavisMMParhamP: T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med1990; 322: 510–517
15.
CharltonBAuchinclossHFathmanCG: Mechanisms of transplantation tolerance. Annu Rev Immunol1994; 12: 707–734
16.
ThompsonCBAllisonJP: The emerging role of CTLA4 as an immune attenuator. Immunity1997; 7: 445–450
17.
LenschowDJWalunasTLBluestoneJA: CD28/B7 system of T cell co-stimulation. Annu Rev Immunol1996; 14: 233–258
18.
PearsonTAlexanderDZCorbascioMHendrixRRitchieSCLinsleyPS: Analysis of the B7 co-stimulatory pathway in allograft rejection. Transplantation1997; 63: 1463–1469
LenschowDJZengYThistlethwaiteJRMontagABradyWGibsonMG: Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science1992; 257: 789–792
21.
SamlowskiWERobertsonBDraperBKPrystasEMcGregorJR: Effects of supravital fluorochromes used to analyze the in vivo homing of murine lymphocytes on cellular function. J Immunol Methods1991; 144: 101–115
22.
PilaroAMLaskinDL: Accumulation of activated mononuclear phagocytes in the liver following lipopolysaccharide treatment of rats. J Leukocyte Biol1986; 40: 29–41
DemetrisAJMuraseNFujisakiSFungJJRaoASStarzlTE: Hematolymphoid cell trafficking, microchimerism and GVH reactions after liver, bone marrow and heart transplantation. Transplant Proc1993; 25: 3337–3344
25.
StarzlTEDemetrisAJMuraseNIidstadSRicordiCTruccoM: Cell migration, chimerism and graft acceptance. Lancet1992; 339: 1579–1582
26.
StarzlTEDemetrisAJTruccoMMuraseNRicordiCIidstadS: Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology1993; 17: 1127–1152
27.
DemetrisAJMuraseNYeQGalvaoFHRichertCSaadR: Analysis of chronic rejection and obliterative arteriopathy. Possible contributions of donor antigen-presenting cells and lymphatic disruption. Am J Pathol1997; 150: 563–578
28.
GrabbeSSteinbrinkKSteinertMLugerTASchwarzT: Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J Immunol1995; 155: 4207–4217
29.
KhourySJGallonLChenWBetresKRussellMEHancockWW: Mechanisms of acquired thymic tolerance in experimental autoimmune encephalomyelitis: thymic dendritic-enriched cells induce specific peripheral T cell unresponsiveness in vivoJ Exp Med1995; 182: 357–366
30.
FinkelmanFDLeesABimbaumRGauseWCMorrisSC: Dendritic cells can present antigen in vivo in a tolerogenic or immunogenic fashion. J Immunol1996; 157: 1406–1414
31.
GrohmannUBianchiRAyroldiEBelladonnaMLSuraceDFiorettiMC: A tumor-associated and self antigen peptide presented by dendritic cells may induce T cell anergy in vivo, but IL-12 can prevent or revert the anergic state. J Immunol1997; 158: 3593–3602
32.
AdlerAJMarshDWYochumGSGuzzoJLNigamANelsonWG: CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells. J Exp Med1998; 187: 1555–1564
33.
SquiersECBrunsonMESalomonDR: Kupffer cells can present alloantigen in vitro: an effect abrogated by gadolinium. J Surg Res1993; 55: 571–574
34.
YuSNakafusaYFlyeMW: Serum suppressive factor appears to potentiate cardiac allograft survival after portal vein injection of ultraviolet B-irradiated donor spleen cells. Transplant Proc1993; 25: 500–501
35.
YangRLiuQGrosfeldJKPescovitzMD: Intestinal venous drainage through the liver is a prerequisite for oral tolerance induction. J Pediatr Surg1994; 29: 1145–1148
36.
CantorHMDumontAE: Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature1967; 215: 744–745
37.
GorczynskiRMChenZZengHFuXM: A role for persisting antigen, antigen presentation, and ICAM-1 in increased renal graft survival after oral or portal vein donor-specific immunization. Transplantation1998; 66: 339–349
38.
SussGShortmanK: A subclass of dendritic cells kills CD4+ T cells via Fas/Fas-ligand-induced apoptosis. J Exp Med1996; 183: 1789–1796
39.
KroninVWinkelKSussGKelsoAHeathWKirbergJ: A subclass of dendritic cells regulates the response of naïve CD8+ T cells by limiting their IL-2 production. J Immunol1996; 157: 3819–3827
KhourySJGallonLVerburgRRChandrakerAPeachRLinsleyPS: Ex vivo treatment of antigen-presenting cells with CTLA4Ig and encephalitogenic peptide prevents experimental autoimmune encephalomyelitis in the Lewis rat. J Immunol1996; 157: 3700–3705
42.
BuelensCVerhasseltVDe GrooteDThielemansKGoldmanMWillemsF: Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by interleukin-10. Eur J Immunol1997; 27: 1848–1852
43.
ThomsonAWLuL: Are dendritic cells the key to liver transplant tolerance?Immunol Today1999; 20: 27–32
44.
MinshallCArkinsSStrazaJConnersJDantzerRFreundGG: IL-4 and insulin-like growth factor-1 inhibit the decline in Bcl2 and promote the survival of IL-3-deprived myeloid progenitors. J Immunol1997; 159: 1225–1232
45.
HuntPEardleyDD: Suppressive effects of insulin and insulin-like growth factor-1 (IGF-1) on immune responses. J Immunol1986; 136: 3994–3999
46.
LuLGambottoALeeWCQianSBonhamCARobbinsPD: Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients. Gene Ther1999; 6: 554–563
47.
TakayamaTNishiokaYLuLLotzeMTTaharaHThomsonAW: Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness. Transplantation1998; 66: 1567–1574
