Absence of Xeno-rejection and Xenoantibody Production in IL-7 KO Recipients After Xenoheart, but not after Xenoskin Transplantation. Shengqiao Li, Yuan Lin, Yehong Yan, Omer Rutgeerts, Caroline Lenaerts, An D Billiau, Mark Waer Laboratory of Experimental Transplantation University of Leuven
Shengqiao Li, Yuan Lin, Yehong Yan, Omer Rutgeerts, Caroline Lenaerts, An D Billiau, Mark Waer
Laboratory of Experimental Transplantation
University of Leuven
It was first discovered in 1988 as a factor that promoted the growth of murine B cell precursors in a bone marrow culture system.
It is a member of the gamma chain-dependent family of cytokines, including IL-2, IL-7, IL-9, and IL-15.
In vivo administration of IL-7 was shown to increases basal proliferation in CD4 and CD8 T cells
the residual splenic T and B cells show normal responsiveness to mitogeneic stimuli.
Carvalho TL et al. Arrested B lymphopoiesis and persistence of activated B cells in adult interleukin 7(-/)- mice. J Exp Med. 2001, 194(8):1141-50.
Tan JT et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A 2001, 98(15):8732-7.
Results: phenotypical analysis of lymphocytes in IL-7 KO mice
Conclusions:1. IL-7 KO mice exhibit a severe reduction of absolute lymphocyte numbers in the spleen, which are 5-10 times lower than IL-7 WT mice.2. Both T and B cells are reduced, while NK cell numbers are not affected.3. As for the B cell subpopulation, MZ B cells are less affected than FO B cells.
in IL-7 KO
in IL-7 WT
Conclusion:1. Xeno-hearts have a long-term survival (>120 days) in IL-7 KO mice. By contrast, IL-7 WT mice reject xeno-hearts as fast as C57BL/6 euthymic mice.2. As T deficient nude mice are able to reject xeno-hearts, the mechanism involved in the failure of IL-7 KO mice to reject xenohearts must involve reasons other than T cell deficiency3. In long-term surviving xenografts, neointima proliferation is found, indicating that IL-7 deficiency does not prevent chronic rejection.
Conclusion :IL-7 KO mice fail to produce high titers of IgM anti-hamster xeno-antibody.
Conclusion:Xeno-skins are rejected after 2-4 months, and associated with delayed IgG Xab production
Conclusion :1. IL-7 KO mice are able to reject xeno-hearts after transfer of naive or presensitized lymphocytes from WT euthymic mice at the day of transplantation. However, they did not reject xenoheart after transfer of lymphocytes from IL-7 KO mice.2. This observation indicates that xenoheart rejection can be triggered in the absence of IL-7.
Conclusion:Lymphocytes from WT euthymic mice and not from IL-7KO mice are able to induce xenoheart rejection in an IL-7 KO environment, even when administered 10 days before transplantation (which may be expected to impair this function when depending on IL-7)
Conclusion:Functional NK xeno-cytotoxicity is normal in IL-7 KO mice
This suggests that qualitative defects in MZB cells or defects in a third factor (other than MZ B and NK cells) are involved in defective IgM Xab induction
on the one hand, the occurence of chronic vascular lesions in long-term xenoheart recipients
on the other hand, the delay in xenoskin rejection
1. IL-7 KO mice (C57BL/6 background) were kindly provided by P Vieira (Paris, France)
2. C57BL/6 euthymic mice, purchased from Harlan (Netherlands).
Xenogeneic donor animals:
1. Inbred golden Syrian hamster, bred locally (University of Leuven).
2. Inbred 30-100g RA rats, bred locally (University of Leuven)
1. Phenotypical analysis IL-7KO mice:
Anti-mouse CD3, CD4,CD8, B220, CD21,CD23, DX5,NK1.1 antibodies ( FITC or PE or Per-cp) purchased from BD Biosciences, Belgium
marginal zone (MZ) B cells are gated as B220+CD21 high CD23low, follicular cells are gated as B220+CD21lowCD23high.
2. Measurement of IgM and IgG xenoantibodies:
Anti-mouse IgM and IgG (FITC), purchased from SeroTec
Splenocytes (+/-lysis of RBC) were injected into the tail vein of recipients.
NK cells were isolated by DX5 microbeads to be used for NK cytotoxicity.