Abstract
Multiple clinical trials have shown the efficacy of adoptively transferred allogeneic antigen-specific T cells for the treatment of viral infections and relapsed hematologic malignancies. In contrast, the therapeutic potential of autologous antigen-specific T cells has yet to be established since it has been technically difficult to generate sufficient numbers of these T cells, ex vivo. A major obstacle to the success of this objective derives from our inability to simply and rapidly isolate and/or expand large numbers of highly efficient antigen presenting cells (APCs) for repetitive stimulations of antigen-specific T cells in vitro. We show that autologous CD40-activated B cells represent a readily available source of highly efficient APC that appear to have several important advantages over other APCs for ex vivo T cell expansion including: (a) methodological simplicity necessary to generate continuously large numbers of APCs from just 50 cm3 of peripheral blood without loss of APC function; (b) capacity to induce high peak T cell proliferation and interferon-gamma production without IL-10 production; (c) ease in cryopreservation; and (d) markedly reduced cost. We, therefore, contend that CD40-activated B cells are an alternative source of highly efficient APCs with which to generate antigen-specific T cells ex vivo for autologous adoptive immunotherapy.
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Selected References
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- Banchereau J., Bazan F., Blanchard D., Brière F., Galizzi J. P., van Kooten C., Liu Y. J., Rousset F., Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922. doi: 10.1146/annurev.iy.12.040194.004313. [DOI] [PubMed] [Google Scholar]
- Banchereau J., Rousset F. Growing human B lymphocytes in the CD40 system. Nature. 1991 Oct 17;353(6345):678–679. doi: 10.1038/353678a0. [DOI] [PubMed] [Google Scholar]
- Banchereau J., de Paoli P., Vallé A., Garcia E., Rousset F. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science. 1991 Jan 4;251(4989):70–72. doi: 10.1126/science.1702555. [DOI] [PubMed] [Google Scholar]
- Bender A., Sapp M., Schuler G., Steinman R. M., Bhardwaj N. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods. 1996 Sep 27;196(2):121–135. doi: 10.1016/0022-1759(96)00079-8. [DOI] [PubMed] [Google Scholar]
- Bertz H., Burger J. A., Kunzmann R., Mertelsmann R., Finke J. Adoptive immunotherapy for relapsed multiple myeloma after allogeneic bone marrow transplantation (BMT): evidence for a graft-versus-myeloma effect. Leukemia. 1997 Feb;11(2):281–283. doi: 10.1038/sj.leu.2400546. [DOI] [PubMed] [Google Scholar]
- Boon T., Cerottini J. C., Van den Eynde B., van der Bruggen P., Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–365. doi: 10.1146/annurev.iy.12.040194.002005. [DOI] [PubMed] [Google Scholar]
- Brossart P., Goldrath A. W., Butz E. A., Martin S., Bevan M. J. Virus-mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL. J Immunol. 1997 Apr 1;158(7):3270–3276. [PubMed] [Google Scholar]
- Caux C., Dezutter-Dambuyant C., Schmitt D., Banchereau J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature. 1992 Nov 19;360(6401):258–261. doi: 10.1038/360258a0. [DOI] [PubMed] [Google Scholar]
- Cella M., Sallusto F., Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol. 1997 Feb;9(1):10–16. doi: 10.1016/s0952-7915(97)80153-7. [DOI] [PubMed] [Google Scholar]
- Celluzzi C. M., Mayordomo J. I., Storkus W. J., Lotze M. T., Falo L. D., Jr Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996 Jan 1;183(1):283–287. doi: 10.1084/jem.183.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Constant S., Schweitzer N., West J., Ranney P., Bottomly K. B lymphocytes can be competent antigen-presenting cells for priming CD4+ T cells to protein antigens in vivo. J Immunol. 1995 Oct 15;155(8):3734–3741. [PubMed] [Google Scholar]
- Flamand V., Sornasse T., Thielemans K., Demanet C., Bakkus M., Bazin H., Tielemans F., Leo O., Urbain J., Moser M. Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo. Eur J Immunol. 1994 Mar;24(3):605–610. doi: 10.1002/eji.1830240317. [DOI] [PubMed] [Google Scholar]
- Giralt S. A., Kolb H. J. Donor lymphocyte infusions. Curr Opin Oncol. 1996 Mar;8(2):96–102. doi: 10.1097/00001622-199603000-00004. [DOI] [PubMed] [Google Scholar]
- Girolomoni G., Ricciardi-Castagnoli P. Dendritic cells hold promise for immunotherapy. Immunol Today. 1997 Mar;18(3):102–104. doi: 10.1016/s0167-5699(97)01030-x. [DOI] [PubMed] [Google Scholar]
- Gollob K. J., Nagelkerken L., Coffman R. L. Endogenous retroviral superantigen presentation by B cells induces the development of type 1 CD4+ T helper lymphocytes. Eur J Immunol. 1993 Oct;23(10):2565–2571. doi: 10.1002/eji.1830231028. [DOI] [PubMed] [Google Scholar]
- Heslop H. E., Ng C. Y., Li C., Smith C. A., Loftin S. K., Krance R. A., Brenner M. K., Rooney C. M. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996 May;2(5):551–555. doi: 10.1038/nm0596-551. [DOI] [PubMed] [Google Scholar]
- Hsu F. J., Benike C., Fagnoni F., Liles T. M., Czerwinski D., Taidi B., Engleman E. G., Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996 Jan;2(1):52–58. doi: 10.1038/nm0196-52. [DOI] [PubMed] [Google Scholar]
- Inaba K., Metlay J. P., Crowley M. T., Steinman R. M. Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ. J Exp Med. 1990 Aug 1;172(2):631–640. doi: 10.1084/jem.172.2.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Inaba K., Metlay J. P., Crowley M. T., Witmer-Pack M., Steinman R. M. Dendritic cells as antigen presenting cells in vivo. Int Rev Immunol. 1990;6(2-3):197–206. doi: 10.3109/08830189009056630. [DOI] [PubMed] [Google Scholar]
- Ke Y., Kapp J. A. Exogenous antigens gain access to the major histocompatibility complex class I processing pathway in B cells by receptor-mediated uptake. J Exp Med. 1996 Sep 1;184(3):1179–1184. doi: 10.1084/jem.184.3.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kolb H. J., Schattenberg A., Goldman J. M., Hertenstein B., Jacobsen N., Arcese W., Ljungman P., Ferrant A., Verdonck L., Niederwieser D. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995 Sep 1;86(5):2041–2050. [PubMed] [Google Scholar]
- Lewalle P., Hensel N., Guimaraes A., Couriel D., Jiang Y Z., Mavroudis D., Barrett A. J. Helper and cytotoxic lymphocyte responses to chronic myeloid leukaemia: implications for adoptive immunotherapy with T cells. Br J Haematol. 1996 Mar;92(3):587–594. [PubMed] [Google Scholar]
- Liu K. J., Parikh V. S., Tucker P. W., Kim B. S. Surface immunoglobulins mediate efficient transport of antigen to lysosomal compartments resulting in enhanced specific antigen presentation by B cells. Eur J Immunol. 1994 Nov;24(11):2755–2760. doi: 10.1002/eji.1830241127. [DOI] [PubMed] [Google Scholar]
- Liu Y. J., Barthélémy C., de Bouteiller O., Arpin C., Durand I., Banchereau J. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity. 1995 Mar;2(3):239–248. doi: 10.1016/1074-7613(95)90048-9. [DOI] [PubMed] [Google Scholar]
- Lucas K. G., Small T. N., Heller G., Dupont B., O'Reilly R. J. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996 Mar 15;87(6):2594–2603. [PubMed] [Google Scholar]
- Matzinger P. The JAM test. A simple assay for DNA fragmentation and cell death. J Immunol Methods. 1991 Dec 15;145(1-2):185–192. doi: 10.1016/0022-1759(91)90325-a. [DOI] [PubMed] [Google Scholar]
- McKeever D. J., Morrison W. I. Immunity to a parasite that transforms T lymphocytes. Curr Opin Immunol. 1994 Aug;6(4):564–567. doi: 10.1016/0952-7915(94)90142-2. [DOI] [PubMed] [Google Scholar]
- Mellado B., Colomer D., Castel T., Muñoz M., Carballo E., Galán M., Mascaró J. M., Vives-Corrons J. L., Grau J. J., Estapé J. Detection of circulating neoplastic cells by reverse-transcriptase polymerase chain reaction in malignant melanoma: association with clinical stage and prognosis. J Clin Oncol. 1996 Jul;14(7):2091–2097. doi: 10.1200/JCO.1996.14.7.2091. [DOI] [PubMed] [Google Scholar]
- Metlay J. P., Puré E., Steinman R. M. Control of the immune response at the level of antigen-presenting cells: a comparison of the function of dendritic cells and B lymphocytes. Adv Immunol. 1989;47:45–116. doi: 10.1016/s0065-2776(08)60662-8. [DOI] [PubMed] [Google Scholar]
- Mitchell R. N., Barnes K. A., Grupp S. A., Sanchez M., Misulovin Z., Nussenzweig M. C., Abbas A. K. Intracellular targeting of antigens internalized by membrane immunoglobulin in B lymphocytes. J Exp Med. 1995 May 1;181(5):1705–1714. doi: 10.1084/jem.181.5.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paglia P., Chiodoni C., Rodolfo M., Colombo M. P. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996 Jan 1;183(1):317–322. doi: 10.1084/jem.183.1.317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Papadopoulos E. B., Ladanyi M., Emanuel D., Mackinnon S., Boulad F., Carabasi M. H., Castro-Malaspina H., Childs B. H., Gillio A. P., Small T. N. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med. 1994 Apr 28;330(17):1185–1191. doi: 10.1056/NEJM199404283301703. [DOI] [PubMed] [Google Scholar]
- Pinkus G. S., Lones M., Shintaku I. P., Said J. W. Immunohistochemical detection of Epstein-Barr virus-encoded latent membrane protein in Reed-Sternberg cells and variants of Hodgkin's disease. Mod Pathol. 1994 May;7(4):454–461. [PubMed] [Google Scholar]
- Porter D. L., Orloff G. J., Antin J. H. Donor mononuclear cell infusions as therapy for B-cell lymphoproliferative disorder following allogeneic bone marrow transplant. Transplant Sci. 1994 Sep;4(1):12–16. [PubMed] [Google Scholar]
- Porter D. L., Roth M. S., McGarigle C., Ferrara J. L., Antin J. H. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994 Jan 13;330(2):100–106. doi: 10.1056/NEJM199401133300204. [DOI] [PubMed] [Google Scholar]
- Riddell S. R., Gilbert M. J., Greenberg P. D. CD8+ cytotoxic T cell therapy of cytomegalovirus and HIV infection. Curr Opin Immunol. 1993 Aug;5(4):484–491. doi: 10.1016/0952-7915(93)90027-p. [DOI] [PubMed] [Google Scholar]
- Riddell S. R., Greenberg P. D. Principles for adoptive T cell therapy of human viral diseases. Annu Rev Immunol. 1995;13:545–586. doi: 10.1146/annurev.iy.13.040195.002553. [DOI] [PubMed] [Google Scholar]
- Riddell S. R., Watanabe K. S., Goodrich J. M., Li C. R., Agha M. E., Greenberg P. D. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science. 1992 Jul 10;257(5067):238–241. doi: 10.1126/science.1352912. [DOI] [PubMed] [Google Scholar]
- Rock K. L., Rothstein L., Gamble S., Fleischacker C. Characterization of antigen-presenting cells that present exogenous antigens in association with class I MHC molecules. J Immunol. 1993 Jan 15;150(2):438–446. [PubMed] [Google Scholar]
- Romani N., Gruner S., Brang D., Kämpgen E., Lenz A., Trockenbacher B., Konwalinka G., Fritsch P. O., Steinman R. M., Schuler G. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994 Jul 1;180(1):83–93. doi: 10.1084/jem.180.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romani N., Koide S., Crowley M., Witmer-Pack M., Livingstone A. M., Fathman C. G., Inaba K., Steinman R. M. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J Exp Med. 1989 Mar 1;169(3):1169–1178. doi: 10.1084/jem.169.3.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Romani N., Reider D., Heuer M., Ebner S., Kämpgen E., Eibl B., Niederwieser D., Schuler G. Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability. J Immunol Methods. 1996 Sep 27;196(2):137–151. doi: 10.1016/0022-1759(96)00078-6. [DOI] [PubMed] [Google Scholar]
- Rooney C. M., Smith C. A., Ng C. Y., Loftin S., Li C., Krance R. A., Brenner M. K., Heslop H. E. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995 Jan 7;345(8941):9–13. doi: 10.1016/s0140-6736(95)91150-2. [DOI] [PubMed] [Google Scholar]
- Sallusto F., Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. doi: 10.1084/jem.179.4.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schultze J. L., Cardoso A. A., Freeman G. J., Seamon M. J., Daley J., Pinkus G. S., Gribben J. G., Nadler L. M. Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8200–8204. doi: 10.1073/pnas.92.18.8200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schultze J. L., Seamon M. J., Michalak S., Gribben J. G., Nadler L. M. Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma cells can be expanded in vitro. Blood. 1997 May 15;89(10):3806–3816. [PubMed] [Google Scholar]
- Siena S., Di Nicola M., Bregni M., Mortarini R., Anichini A., Lombardi L., Ravagnani F., Parmiani G., Gianni A. M. Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. Exp Hematol. 1995 Dec;23(14):1463–1471. [PubMed] [Google Scholar]
- Steinman R. M., Witmer-Pack M., Inaba K. Dendritic cells: antigen presentation, accessory function and clinical relevance. Adv Exp Med Biol. 1993;329:1–9. doi: 10.1007/978-1-4615-2930-9_1. [DOI] [PubMed] [Google Scholar]
- Szabolcs P., Avigan D., Gezelter S., Ciocon D. H., Moore M. A., Steinman R. M., Young J. W. Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate. Blood. 1996 Jun 1;87(11):4520–4530. [PubMed] [Google Scholar]
- Szabolcs P., Moore M. A., Young J. W. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-alpha. J Immunol. 1995 Jun 1;154(11):5851–5861. [PubMed] [Google Scholar]
- Topalian S. L., Rivoltini L., Mancini M., Ng J., Hartzman R. J., Rosenberg S. A. Melanoma-specific CD4+ T lymphocytes recognize human melanoma antigens processed and presented by Epstein-Barr virus-transformed B cells. Int J Cancer. 1994 Jul 1;58(1):69–79. doi: 10.1002/ijc.2910580113. [DOI] [PubMed] [Google Scholar]
- Verdonck L. F., Lokhorst H. M., Dekker A. W., Nieuwenhuis H. K., Petersen E. J. Graft-versus-myeloma effect in two cases. Lancet. 1996 Mar 23;347(9004):800–801. doi: 10.1016/s0140-6736(96)90871-5. [DOI] [PubMed] [Google Scholar]
- Vidard L., Kovacsovics-Bankowski M., Kraeft S. K., Chen L. B., Benacerraf B., Rock K. L. Analysis of MHC class II presentation of particulate antigens of B lymphocytes. J Immunol. 1996 Apr 15;156(8):2809–2818. [PubMed] [Google Scholar]
- Visseren M. J., van Elsas A., van der Voort E. I., Ressing M. E., Kast W. M., Schrier P. I., Melief C. J. CTL specific for the tyrosinase autoantigen can be induced from healthy donor blood to lyse melanoma cells. J Immunol. 1995 Apr 15;154(8):3991–3998. [PubMed] [Google Scholar]
- Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038–1044. doi: 10.1056/NEJM199510193331603. [DOI] [PubMed] [Google Scholar]
- Yee C., Gilbert M. J., Riddell S. R., Brichard V. G., Fefer A., Thompson J. A., Boon T., Greenberg P. D. Isolation of tyrosinase-specific CD8+ and CD4+ T cell clones from the peripheral blood of melanoma patients following in vitro stimulation with recombinant vaccinia virus. J Immunol. 1996 Nov 1;157(9):4079–4086. [PubMed] [Google Scholar]
- Young J. W., Szabolcs P., Moore M. A. Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med. 1995 Oct 1;182(4):1111–1119. doi: 10.1084/jem.182.4.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]