Genetically modified human CD4+ T cells can be evaluated in vivo without lethal graft-versus-host disease

Riyasat Ali, Jeffrey Babad, Antonia Follenzi, John A. Gebe, Michael A. Brehm, Gerald T. Nepom, Leonard D. Shultz, Dale L. Greiner, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Adoptive cell immunotherapy for human diseases, including the use of T cells modified to express an anti-tumour T-cell receptor (TCR) or chimeric antigen receptor, is showing promise as an effective treatment modality. Further advances would be accelerated by the availability of a mouse model that would permit human T-cell engineering protocols and proposed genetic modifications to be evaluated in vivo. NOD-scid IL2rγnull (NSG) mice accept the engraftment of mature human T cells; however, long-term evaluation of transferred cells has been hampered by the xenogeneic graft-versus-host disease (GVHD) that occurs soon after cell transfer. We modified human primary CD4+ T cells by lentiviral transduction to express a human TCR that recognizes a pancreatic beta cell-derived peptide in the context of HLA-DR4. The TCR-transduced cells were transferred to NSG mice engineered to express HLA-DR4 and to be deficient for murine class II MHC molecules. CD4+ T-cell-depleted peripheral blood mononuclear cells were also transferred to facilitate engraftment. The transduced cells exhibited long-term survival (up to 3 months post-transfer) and lethal GVHD was not observed. This favourable outcome was dependent upon the pre-transfer T-cell transduction and culture conditions, which influenced both the kinetics of engraftment and the development of GVHD. This approach should now permit human T-cell transduction protocols and genetic modifications to be evaluated in vivo, and it should also facilitate the development of human disease models that incorporate human T cells.

Original languageEnglish (US)
Pages (from-to)339-351
Number of pages13
JournalImmunology
Volume148
Issue number4
DOIs
StatePublished - Aug 1 2016

Keywords

  • human CD4 T cells
  • immunodeficient mice
  • lentiviral transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ali, R., Babad, J., Follenzi, A., Gebe, J. A., Brehm, M. A., Nepom, G. T., Shultz, L. D., Greiner, D. L., & DiLorenzo, T. P. (2016). Genetically modified human CD4+ T cells can be evaluated in vivo without lethal graft-versus-host disease. Immunology, 148(4), 339-351. https://doi.org/10.1111/imm.12613