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Pre-Clinical Studies

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

Bone Marrow Transplantation volume 46, pages 586–596 (2011)Cite this article

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Abstract

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

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Acknowledgements

This work was supported by grants from the FWO Vlaanderen, the Stichting tegen Kanker and the WOMS (Scientific Research Multiple Sclerosis). BS and BVW are doctoral fellows and ADB is a postdoctoral fellow of the FWO Vlaanderen. AL and BV are doctoral fellows of IWT. BD is supported by the University Research Council of the University of Leuven, Belgium.

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Author notes

  1. B Sprangers, B Van Wijmeersch and A Luyckx: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium

    B Sprangers, B Van Wijmeersch, A Luyckx, O Rutgeerts, C Lenaerts, M Waer & A D Billiau

  2. Laboratory of Neuroimmunology, University of Leuven, Leuven, Belgium

    B Van Wijmeersch & B Dubois

  3. Department of Pathology, University of Leuven, Leuven, Belgium

    X Sagaert & T Tousseyn

  4. Laboratory of Experimental Immunology, University of Leuven, Leuven, Belgium

    B Verbinnen

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  1. B Sprangers
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Correspondence to A D Billiau.

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Sprangers, B., Van Wijmeersch, B., Luyckx, A. et al. Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction. Bone Marrow Transplant 46, 586–596 (2011). https://doi.org/10.1038/bmt.2010.162

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