Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Jun 1;177(6):1681–1690. doi: 10.1084/jem.177.6.1681

An evaluation of the potential to use tumor-associated antigens as targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues

PMCID: PMC2191055  PMID: 8496686

Abstract

A major obstacle to the development of T cell therapy for the treatment of human tumors has been the difficulty generating T cells specifically reactive with the tumor. Most of the characterized human tumor antigens have been classified as tumor associated, because of demonstrable expression at low levels in some normal cells, and thus have not been extensively studied as potential targets of a therapeutic immune response. However, the quantitative difference in expression of such antigens between the tumor and normal cells might permit the generation of antigen-specific T cells capable of selective antitumor and not autoimmune activity. To address this issue, transgenic (TG) mice were generated that expressed low levels of Friend murine leukemia virus (FMuLV) envelope protein in lymphoid cells under the control of an immunoglobulin promoter. This protein is expressed at high levels by a Friend virus-induced erythroleukemia of C57BL/6 (B6) origin, FBL, and has been shown to serve as an efficient tumor-specific rejection antigen in B6 mice. The env-TG mice were tolerant to envelope, as reflected by the failure to detect an envelope-specific response after in vivo priming and in vitro stimulation with preparations of FMuLV envelope. However, adoptively transferred envelope-specific T cells from immunized non-TG B6 mice mediated complete eradication of FBL tumor cells in TG mice, and did not induce detectable autoimmune damage to TG lymphoid tissues. The transferred immune cells were not permanently inactivated in the TG mice, since donor T cells responded to envelope after removal from the TG mice. The lack of autoimmune injury did not reflect inadequate expression of envelope by TG lymphocytes for recognition by T cells, since TG lymphocytes functioned effectively in vitro as stimulators for envelope-specific T cells. The results suggest that this and analogous strains of TG mice may prove useful for elucidating principles for the generation and therapeutic use of tumor-reactive T cells specific for tumor-associated antigens.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bookman M. A., Swerdlow R., Matis L. A. Adoptive chemoimmunotherapy of murine leukemia with helper T lymphocyte clones. J Immunol. 1987 Nov 1;139(9):3166–3170. [PubMed] [Google Scholar]
  3. Brinster R. L., Allen J. M., Behringer R. R., Gelinas R. E., Palmiter R. D. Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci U S A. 1988 Feb;85(3):836–840. doi: 10.1073/pnas.85.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Böhme J., Schuhbaur B., Kanagawa O., Benoist C., Mathis D. MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science. 1990 Jul 20;249(4966):293–295. doi: 10.1126/science.2115690. [DOI] [PubMed] [Google Scholar]
  6. Chaffin K. E., Beals C. R., Wilkie T. M., Forbush K. A., Simon M. I., Perlmutter R. M. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 1990 Dec;9(12):3821–3829. doi: 10.1002/j.1460-2075.1990.tb07600.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen W., Reese V. A., Cheever M. A. Adoptively transferred antigen-specific T cells can be grown and maintained in large numbers in vivo for extended periods of time by intermittent restimulation with specific antigen plus IL-2. J Immunol. 1990 May 15;144(10):3659–3666. [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Dallman M. J., Shiho O., Page T. H., Wood K. J., Morris P. J. Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway. J Exp Med. 1991 Jan 1;173(1):79–87. doi: 10.1084/jem.173.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Earl P. L., Moss B., Morrison R. P., Wehrly K., Nishio J., Chesebro B. T-lymphocyte priming and protection against Friend leukemia by vaccinia-retrovirus env gene recombinant. Science. 1986 Nov 7;234(4777):728–731. doi: 10.1126/science.3490689. [DOI] [PubMed] [Google Scholar]
  11. Fefer A., Einstein A. B., Jr, Cheever M. A., Berenson J. R. Models for syngeneic adoptive chemoimmunotherapy of murine leukemias. Ann N Y Acad Sci. 1976;276:573–583. doi: 10.1111/j.1749-6632.1976.tb41684.x. [DOI] [PubMed] [Google Scholar]
  12. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  13. Gammon G., Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. doi: 10.1038/342183a0. [DOI] [PubMed] [Google Scholar]
  14. Gillies S. D., Morrison S. L., Oi V. T., Tonegawa S. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell. 1983 Jul;33(3):717–728. doi: 10.1016/0092-8674(83)90014-4. [DOI] [PubMed] [Google Scholar]
  15. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  16. Greenberg P. D. Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol. 1991;49:281–355. doi: 10.1016/s0065-2776(08)60778-6. [DOI] [PubMed] [Google Scholar]
  17. Greenberg P. D., Cheever M. A., Fefer A. Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes. J Exp Med. 1981 Sep 1;154(3):952–963. doi: 10.1084/jem.154.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Greenberg P. D., Cheever M. A. Treatment of disseminated leukemia with cyclophosphamide and immune cells: tumor immunity reflects long-term persistence of tumor-specific donor T cells. J Immunol. 1984 Dec;133(6):3401–3407. [PubMed] [Google Scholar]
  19. Greenberg P. D., Kern D. E., Cheever M. A. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med. 1985 May 1;161(5):1122–1134. doi: 10.1084/jem.161.5.1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Greenberg P. D. Therapy of murine leukemia with cyclophosphamide and immune Lyt-2+ cells: cytolytic T cells can mediate eradication of disseminated leukemia. J Immunol. 1986 Mar 1;136(5):1917–1922. [PubMed] [Google Scholar]
  21. Grosschedl R., Baltimore D. Cell-type specificity of immunoglobulin gene expression is regulated by at least three DNA sequence elements. Cell. 1985 Jul;41(3):885–897. doi: 10.1016/s0092-8674(85)80069-6. [DOI] [PubMed] [Google Scholar]
  22. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  23. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  24. Kern D. E., Peace D. J., Klarnet J. P., Cheever M. A., Greenberg P. D. Il-4 is an endogenous T cell growth factor during the immune response to a syngeneic retrovirus-induced tumor. J Immunol. 1988 Oct 15;141(8):2824–2830. [PubMed] [Google Scholar]
  25. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  26. Klarnet J. P., Kern D. E., Okuno K., Holt C., Lilly F., Greenberg P. D. FBL-reactive CD8+ cytotoxic and CD4+ helper T lymphocytes recognize distinct Friend murine leukemia virus-encoded antigens. J Exp Med. 1989 Feb 1;169(2):457–467. doi: 10.1084/jem.169.2.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Koch W., Hunsmann G., Friedrich R. Nucleotide sequence of the envelope gene of Friend murine leukemia virus. J Virol. 1983 Jan;45(1):1–9. doi: 10.1128/jvi.45.1.1-9.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Korngold R., Sprent J. Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences. J Immunol. 1985 Nov;135(5):3004–3010. [PubMed] [Google Scholar]
  29. Lo D., Burkly L. C., Flavell R. A., Palmiter R. D., Brinster R. L. Tolerance in transgenic mice expressing class II major histocompatibility complex on pancreatic acinar cells. J Exp Med. 1989 Jul 1;170(1):87–104. doi: 10.1084/jem.170.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lo D., Burkly L. C., Widera G., Cowing C., Flavell R. A., Palmiter R. D., Brinster R. L. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell. 1988 Apr 8;53(1):159–168. doi: 10.1016/0092-8674(88)90497-7. [DOI] [PubMed] [Google Scholar]
  31. Markmann J., Lo D., Naji A., Palmiter R. D., Brinster R. L., Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature. 1988 Dec 1;336(6198):476–479. doi: 10.1038/336476a0. [DOI] [PubMed] [Google Scholar]
  32. Morahan G., Allison J., Miller J. F. Tolerance of class I histocompatibility antigens expressed extrathymically. Nature. 1989 Jun 22;339(6226):622–624. doi: 10.1038/339622a0. [DOI] [PubMed] [Google Scholar]
  33. Morahan G., Brennan F. E., Bhathal P. S., Allison J., Cox K. O., Miller J. F. Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter. Proc Natl Acad Sci U S A. 1989 May;86(10):3782–3786. doi: 10.1073/pnas.86.10.3782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Murphy K. M., Weaver C. T., Elish M., Allen P. M., Loh D. Y. Peripheral tolerance to allogeneic class II histocompatibility antigens expressed in transgenic mice: evidence against a clonal-deletion mechanism. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10034–10038. doi: 10.1073/pnas.86.24.10034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nossal G. J. Immunologic tolerance: collaboration between antigen and lymphokines. Science. 1989 Jul 14;245(4914):147–153. doi: 10.1126/science.2526369. [DOI] [PubMed] [Google Scholar]
  36. OLINER H., SCHWARTZ R., DAMESHEK W. Studies in experimental autoimmune disorders. I. Clinical and laboratory features of autoimmunization (runt disease) in the mouse. Blood. 1961 Jan;17:20–44. [PubMed] [Google Scholar]
  37. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  38. Oldstone M. B., Nerenberg M., Southern P., Price J., Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. doi: 10.1016/0092-8674(91)90165-u. [DOI] [PubMed] [Google Scholar]
  39. Sandgren E. P., Luetteke N. C., Palmiter R. D., Brinster R. L., Lee D. C. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990 Jun 15;61(6):1121–1135. doi: 10.1016/0092-8674(90)90075-p. [DOI] [PubMed] [Google Scholar]
  40. Schild H., Rötzschke O., Kalbacher H., Rammensee H. G. Limit of T cell tolerance to self proteins by peptide presentation. Science. 1990 Mar 30;247(4950):1587–1589. doi: 10.1126/science.2321019. [DOI] [PubMed] [Google Scholar]
  41. Schreiber H., Ward P. L., Rowley D. A., Stauss H. J. Unique tumor-specific antigens. Annu Rev Immunol. 1988;6:465–483. doi: 10.1146/annurev.iy.06.040188.002341. [DOI] [PubMed] [Google Scholar]
  42. Schwartz R. H. Acquisition of immunologic self-tolerance. Cell. 1989 Jun 30;57(7):1073–1081. doi: 10.1016/0092-8674(89)90044-5. [DOI] [PubMed] [Google Scholar]
  43. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  44. Seeburg P. H. The human growth hormone gene family: nucleotide sequences show recent divergence and predict a new polypeptide hormone. DNA. 1982;1(3):239–249. doi: 10.1089/dna.1.1982.1.239. [DOI] [PubMed] [Google Scholar]
  45. Shimizu Y., van Seventer G. A., Horgan K. J., Shaw S. Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation. Immunol Rev. 1990 Apr;114:109–143. doi: 10.1111/j.1600-065x.1990.tb00563.x. [DOI] [PubMed] [Google Scholar]
  46. Shulman M., Wilde C. D., Köhler G. A better cell line for making hybridomas secreting specific antibodies. Nature. 1978 Nov 16;276(5685):269–270. doi: 10.1038/276269a0. [DOI] [PubMed] [Google Scholar]
  47. Sissons J. G., Oldstone M. B., Schreiber R. D. Antibody-independent activation of the alternative complement pathway by measles virus-infected cells. Proc Natl Acad Sci U S A. 1980 Jan;77(1):559–562. doi: 10.1073/pnas.77.1.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  49. Tepper R. I., Levinson D. A., Stanger B. Z., Campos-Torres J., Abbas A. K., Leder P. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990 Aug 10;62(3):457–467. doi: 10.1016/0092-8674(90)90011-3. [DOI] [PubMed] [Google Scholar]
  50. Thiele D. L., Bryde S. E., Lipsky P. E. Lethal graft-vs-host disease induced by a class II MHC antigen only disparity is not mediated by cytotoxic T cells. J Immunol. 1988 Nov 15;141(10):3377–3382. [PubMed] [Google Scholar]
  51. Wysocki L. J., Sato V. L. "Panning" for lymphocytes: a method for cell selection. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2844–2848. doi: 10.1073/pnas.75.6.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES