Enhancement of Antigen-specific Antibody and $CD8^+$ T Cell Responses by Codelivery of IL-12-encapsulated Microspheres in Protein and Peptide Vaccination

  • Park, Su-Hyung (Division of Molecular and Life Sciences, Postech Biotech Center, Pohang University of Science & Technology) ;
  • Chang, Jun (College of Pharmacy, Ewha Womans University) ;
  • Yang, Se-Hwan (Division of Molecular and Life Sciences, Postech Biotech Center, Pohang University of Science & Technology) ;
  • Kim, Hye-Ju (Division of Molecular and Life Sciences, Postech Biotech Center, Pohang University of Science & Technology) ;
  • Kwak, Hyun-Hee (Research Laboratories, Dong-A Pham. Co., Ltd.) ;
  • Kim, Byong-Moon (Research Laboratories, Dong-A Pham. Co., Ltd.) ;
  • Lee, Sung-Hee (Research Laboratories, Dong-A Pham. Co., Ltd.) ;
  • Sung, Young-Chul (Division of Molecular and Life Sciences, Postech Biotech Center, Pohang University of Science & Technology)
  • Published : 2007.12.31

Abstract

Background: Although IL-12 has been widely accepted to playa central role in the control of pathogen infection, the use of recombinant IL-12 (rIL-12) as a vaccine adjuvant has been known to be ineffective because of its rapid clearance in the body. Methods: To investigate the effect of sustained release of IL-12 in vivo in the peptide and protein vaccination models, rIL-12 was encapsulated into poly ($A_{DL}$-lactic-co-glycolic acid) (PLGA). Results: We found that codelivery of IL-12-encapsulated microspheres (IL-12EM) could dramatically increase not only antibody responses, but also antigen-specific $CD4^+\;and\;CD8^+$ T cell responses. Enhanced immune responses were shown to be correlated with protective immunity against influenza and respiratory syncytial virus (RSV) virus challenge. Interestingly, the enhancement of $CD8^+$ T cell response was not detectable when $CD4^+$ T cell knockout mice were subjected to vaccination, indicating that the enhancement of the $CD8^+$ T cell response by IL-12EM is dependent on $CD4^+$ T cell "help". Conclusion: Thus, IL-12EM could be applied as an adjuvant of protein and peptide vaccines to enhance protective immunity against virus infection.

Keywords

References

  1. Afonso LC, Scharton TM, Vieira LQ, Wysocka M, Trinchieri G, Scott P: The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263;235-237, 1994 https://doi.org/10.1126/science.7904381
  2. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, McMichael AJ, Davis MM: Phenotypic analysis of antigen-specific T lymphocytes. Science 274;94-96, 1996 https://doi.org/10.1126/science.274.5284.94
  3. Athie-Morales V, Smits HH, Cantrell DA, Hilkens CM: Sustained IL-12 signaling is required for Th1 development. J Immunol 172;61-69, 2004 https://doi.org/10.4049/jimmunol.172.1.61
  4. Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR: Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med 186;65-70, 1997 https://doi.org/10.1084/jem.186.1.65
  5. Berzofsky JA, Ahlers JD, Belyakov IM: Strategies for designing and optimizing new generation vaccines. Nat Rev Immunol 1;209-219, 2001 https://doi.org/10.1038/35105075
  6. Bliss J, Van Cleave V, Murray K, Wiencis A, Ketchum M, Maylor R, Haire T, Resmini C, Abbas AK, Wolf SF: IL-12, as an adjuvant, promotes a T helper 1 cell, but does not suppress a T helper 2 cell recall response. J Immunol 156;887-894, 1996
  7. Chang J, Choi SY, Jin HT, Sung YC, Braciale TJ: Improved effector activity and memory CD8 T cell development by IL-2 expression during experimental respiratory syncytial virus infection. J Immunol 172;503-508, 2004 https://doi.org/10.4049/jimmunol.172.1.503
  8. Crotts G, Park TG: Protein delivery from poly (lactic-co-glycolic acid) biodegradable microspheres: release kinetics and stability issues. J Microencapsul 15;699-713, 1998 https://doi.org/10.3109/02652049809008253
  9. 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 162;3256-3262, 1999
  10. Datta SK, Redecke V, Prilliman KR, Takabayashi K, Corr M, Tallant T, DiDonato J, Dziarski R, Akira S, Schoenberger SP, Raz E: A subset of Toll-like receptor ligands induces crosspresentation by bone marrow-derived dendritic cells. J Immunol 170;4102-4110, 2003 https://doi.org/10.4049/jimmunol.170.8.4102
  11. den Haan JM, Bevan MJ: Constitutive versus activation-dependent cross-presentation of immune complexes by CD8(+) and CD8(+) dendritic cells in vivo. J Exp Med 196;817-827, 2002 https://doi.org/10.1084/jem.20020295
  12. Egilmez NK, Jong YS, Sabel MS, Jacob JS, Mathiowitz E, Bankert RB: In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity. Cancer Res 60;3832-3837, 2000
  13. Fayolle C, Deriaud E, Leclerc C: In vivo induction of cytotoxic T cell response by a free synthetic peptide requires CD4+ T cell help. J Immunol 147;4069-4073, 1991
  14. Guerder S, Matzinger P: A fail-safe mechanism for maintaining self-tolerance. J Exp Med 176;553-564, 1992 https://doi.org/10.1084/jem.176.2.553
  15. Gurunathan S, Prussin C, Sacks DL, Seder RA: Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection. Nat Med 4;1409-1415, 1998 https://doi.org/10.1038/4000
  16. Ha SJ, Chang J, Song MK, Suh YS, Jin HT, Lee CH, Nam GH, Choi G, Choi KY, Lee SH, Kim WB, Sung YC: Engineering N-glycosylation mutations in IL-12 enhances sustained cytotoxic T lymphocyte responses for DNA immunization. Nat Biotechnol 20;381-386, 2002 https://doi.org/10.1038/nbt0402-381
  17. Ha SJ, Park SH, Kim HJ, Kim SC, Kang HJ, Lee EG, Kwon SG, Kim BM, Lee SH, Kim WB, Sung YC, Cho SN: Enhanced immunogenicity and protective efficacy with the use of interleukin-12-encapsulated microspheres plus AS01B in tuberculosis subunit vaccination. Infect Immun 74;4954-4959, 2006 https://doi.org/10.1128/IAI.01781-05
  18. Hamajima K, Fukushima J, Bukawa H, Kaneko T, Tsuji T, Asakura Y, Sasaki S, Xin KQ, Okuda K: Strong augment effect of IL-12 expression plasmid on the induction of HIVspecific cytotoxic T lymphocyte activity by a peptide vaccine candidate. Clin Immunol Immunopathol 83;179-184, 1997 https://doi.org/10.1006/clin.1997.4348
  19. Haskova Z, Usiu N, Pepose JS, Ferguson TA, Stuart PM: CD4+ T cells are critical for corneal, but not skin, allograft rejection. Transplantation 69;483-487, 2000 https://doi.org/10.1097/00007890-200002270-00004
  20. Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK: Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med 177;1505-1509, 1993 https://doi.org/10.1084/jem.177.5.1505
  21. Hill HC, Conway TF Jr, Sabel MS, Jong YS, Mathiowitz E, Bankert RB, Egilmez NK: Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. Cancer Res 62;7254-7263, 2002
  22. Kim TH, Park TG: Critical effect of freezing/freeze-drying on sustained release of FITC-dextran encapsulated within PLGA microspheres. Int J Pharm 271;207-214, 2004 https://doi.org/10.1016/j.ijpharm.2003.11.021
  23. Knutson KL, Schiffman K, Disis ML: Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients. J Clin Invest 107;477-484, 2001 https://doi.org/10.1172/JCI11752
  24. Kubin M, Chow JM, Trinchieri G: Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells. Blood 83;1847-1855, 1994
  25. Kurts C, Carbone FR, Barnden M, Blanas E, Allison J, Heath WR, Miller JF: CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity. J Exp Med 186;2057-2062, 1997 https://doi.org/10.1084/jem.186.12.2057
  26. Kyburz D, Aichele P, Speiser DE, Hengartner H, Zinkernagel RM, Pircher H: T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur J Immunol 23;1956-1962, 1993 https://doi.org/10.1002/eji.1830230834
  27. Langer R: Biomaterials in drug delivery and tissue engineering: one laboratory's experience. Acc Chem Res 33;94-101, 2000 https://doi.org/10.1021/ar9800993
  28. Langer R: Drug delivery and targeting. Nature 392;5-10, 1998
  29. Lee SW, Youn JW, Seong BL, Sung YC: IL-6 induces longterm protective immunity against a lethal challenge of influenza virus. Vaccine 17;490-496, 1999 https://doi.org/10.1016/S0264-410X(98)00223-0
  30. Lindblad EB, Elhay MJ, Silva R, Appelberg R, Andersen P: Adjuvant modulation of immune responses to tuberculosis subunit vaccines. Infect Immun 65;623-629, 1997
  31. Ma X, Chow JM, Gri G, Carra G, Gerosa F, Wolf SF, Dzialo R, Trinchieri G: The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med 183;147-157, 1996 https://doi.org/10.1084/jem.183.1.147
  32. Machy P, Serre K, Baillet M, Leserman L: Induction of MHC class I presentation of exogenous antigen by dendritic cells is controlled by CD4+ T cells engaging class II molecules in cholesterol-rich domains. J Immunol 168;1172-1180, 2002 https://doi.org/10.4049/jimmunol.168.3.1172
  33. Machy P, Serre K, Leserman L: Class I-restricted presentation of exogenous antigen acquired by Fcgamma receptor-mediated endocytosis is regulated in dendritic cells. Eur J Immunol 30;848-857, 2000 https://doi.org/10.1002/1521-4141(200003)30:3<848::AID-IMMU848>3.0.CO;2-Q
  34. Park SH, Yang SH, Lee CG, Youn JW, Chang J, Sung YC: Efficient induction of T helper 1 CD4+ T-cell responses to hepatitis C virus core and E2 by a DNA prime-adenovirus boost. Vaccine 21;4555-4564, 2003 https://doi.org/10.1016/S0264-410X(03)00499-7
  35. Partidos CD, Vohra P, Jones D, Farrar G, Steward MW: CTL responses induced by a single immunization with peptide encapsulated in biodegradable microparticles. J Immunol Methods 206;143-151, 1997 https://doi.org/10.1016/S0022-1759(97)00102-6
  36. Putney SD, Burke PA: Improving protein therapeutics with sustained-release formulations. Nat Biotechnol 16;153-157, 1998 https://doi.org/10.1038/nbt0298-153
  37. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393;480-483, 1998 https://doi.org/10.1038/31002
  38. Serre K, Giraudo L, Siret C, Leserman L, Machy P: CD4 T cell help is required for primary CD8 T cell responses to vesicular antigen delivered to dendritic cells in vivo. Eur J Immunol 36;1386-1397, 2006 https://doi.org/10.1002/eji.200526193
  39. Song K, Chang Y, Prud'homme GJ: IL-12 plasmid-enhanced DNA vaccination against carcinoembryonic antigen (CEA) studied in immune-gene knockout mice. Gene Ther 7;1527-1535, 2000 https://doi.org/10.1038/sj.gt.3301274
  40. Stuhler G, Schlossman SF: Antigen organization regulates cluster formation and induction of cytotoxic T lymphocytes by helper T cell subsets. Proc Natl Acad Sci U S A 94;622-627, 1997
  41. Vogel LA, Showe LC, Lester TL, McNutt RM, Van Cleave VH, Metzger DW: Direct binding of IL-12 to human and murine B lymphocytes. Int Immunol 8;1955-1962, 1996 https://doi.org/10.1093/intimm/8.12.1955
  42. Wild J, Grusby MJ, Schirmbeck R, Reimann J: Priming MHCI-restricted cytotoxic T lymphocyte responses to exogenous hepatitis B surface antigen is CD4+ T cell dependent. J Immunol 163;1880-1887, 1999
  43. Yap G, Pesin M, Sher A: Cutting edge: IL-12 is required for the maintenance of IFN-gamma production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J Immunol 165;628-631, 2000 https://doi.org/10.4049/jimmunol.165.2.628
  44. Youn JW, Park SH, Lavillette D, Cosset FL, Yang SH, Lee CG, Jin HT, Kim CM, Shata MT, Lee DH, Pfahler W, Prince AM, Sung YC: Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee. Hepatology 42;1429-1436, 2005 https://doi.org/10.1002/hep.20934