Your browser doesn't support javascript.
loading
Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells.
Distler, Eva; Bloetz, Andrea; Albrecht, Jana; Asdufan, Saliha; Hohberger, Alexander; Frey, Michaela; Schnürer, Elke; Thomas, Simone; Theobald, Matthias; Hartwig, Udo F; Herr, Wolfgang.
Affiliation
  • Distler E; 3rd Department of Medicine, University Medical Center of Johannes Gutenberg-University, Mainz, Germany.
Haematologica ; 96(7): 1024-32, 2011 Jul.
Article in En | MEDLINE | ID: mdl-21486863
ABSTRACT

BACKGROUND:

HLA mismatch antigens are major targets of alloreactive T cells in HLA-incompatible stem-cell transplantation, which can trigger severe graft-versus-host disease and reduce survival in transplant recipients. Our objective was to identify T-cell subsets with reduced in vitro reactivity to allogeneic HLA antigens. DESIGN AND

METHODS:

We sorted CD4 and CD8 T-cell subsets from peripheral blood by flow cytometry according to their expression of naive and memory markers CD45RA, CD45RO, CD62L, and CCR7. Subsets were defined by a single marker to facilitate future establishment of a clinical-grade procedure for reducing alloreactive T-cell precursors and graft-versus-host disease. T cells were stimulated in mixed lymphocyte reactions against HLA-deficient K562 cells transfected with single HLA-A/-B/-C/-DR/-DQ mismatch alleles. Alloreactivity was measured by interferon-γ spot production and cell proliferation.

RESULTS:

We observed that allogeneic HLA-reactivity was preferentially derived from subsets enriched for naïve T cells rather than memory T cells in healthy donors, irrespective of the HLA mismatch allele. This separation was most efficient if CD45RA (versus other markers) was used for sorting. The numbers of allogeneic HLA-reactive effector cells were in median 7.2-fold and 16.6-fold lower in CD45RA(neg) memory CD8 and CD4 T cells than in entire CD8 and CD4 T cells, respectively. In contrast, proliferation of memory T cells in response to allogeneic HLA was more variably reduced (CD8) or equivalent (CD4) when compared to that of naïve T cells. We also demonstrated in HLA-matched donor-patient pairs that leukemia-reactive CD8 cytotoxic T-lymphocytes were mainly derived from subsets enriched for naïve T cells compared to memory T cells.

CONCLUSIONS:

Memory T-cell subsets of most healthy individuals showed decreased allogeneic HLA-reactivity, but lacked significant anti-leukemia responses in vitro. The clinical use of memory or naïve-depleted T cells might be beneficial for HLA-mismatched patients at high risk of graft-versus-host disease and low risk of leukemia relapse. Preferred allografts are those which contain leukemia-reactive memory T cells. Alternatively, replenishment with leukemia-reactive T cells isolated from naïve subsets is desirable.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Tissue Donors / T-Lymphocytes / Leukemia / Precursor Cells, T-Lymphoid / Immunologic Memory / Immunotherapy Limits: Humans Language: En Journal: Haematologica Year: 2011 Type: Article Affiliation country: Germany

Full text: 1 Database: MEDLINE Main subject: Tissue Donors / T-Lymphocytes / Leukemia / Precursor Cells, T-Lymphoid / Immunologic Memory / Immunotherapy Limits: Humans Language: En Journal: Haematologica Year: 2011 Type: Article Affiliation country: Germany