Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into scid mice

Changqing Xun, Stephen A. Brown, C. Darrell Jennings, P. Jean Henslee-Downey, John S. Thompson

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39 Scopus citations

Abstract

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody-and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70–95% of NK-enriched cells expressed CDS-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-α/β+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40–50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-α cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-γ was increased in both NK and T cells. After i.v. injection of 1–5 ± 107 cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK-but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-α, and IFN-γ antibodies demonstrated CD56+ cells in association with TNF-α and IFN-γ secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.

Original languageEnglish
Pages (from-to)409-417
Number of pages9
JournalTransplantation
Volume56
Issue number2
DOIs
StatePublished - Aug 1993

ASJC Scopus subject areas

  • Transplantation

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