Abstract
Mixed chimerism is a potential induction method for alloantigen-specific tolerance. Although the phenomenon has been broadly studied over recent years, some important aspects remain to be elucidated. The aim of our study was to identify the optimal mouse stem/progenitor cell population for mixed chimerism induction purposes. To induce stable mixed chimerism, B6.SJL-PtprcaPep3b (CD45.1; H-2s; I-E-) mice were exposed to 3-Gy total body irradiation (Day -1) as well as the CD40L (Day 0, and 4) and CD8 (Day -2) blocking antibodies. The animals were transplanted with 10×106 Balb/c (CD45.2; H-2d; I-E+) unfractionated bone marrow cells (Day 0). Since mouse stem/progenitor cells are found among lin- population and they possess Sca-1 and c-kit antigens, mice were given 2×105 of lin-/Sca-1+/c-kit-, lin-/Sca-1+/c-kit+ or lin-/Sca-1-/c-kit+ bone marrow-derived cells. Mixed chimerism was measured in peripheral blood leukocytes several times during the 26-week experiment. In addition, the chimerism rate and the kinetics of the percentage of CD4, CD8 and NK1.1 cells in the peripheral blood were assessed. The tolerance to Balb/c mouse antigens induced by the stem/progenitor cells was tested by analyzing the proportions of the Vβ5 and Vβ11 TCR-expressing lymphocytes as well as by assessing skin graft (Day 0) acceptance. The lin-/Sca-1+/c-kit+ and lin-/Sca-1-/c-kit+ cells, but not the lin-/Sca-1+/c-kit- cells, induced a high degree of stable (26 weeks) multilineage mixed chimerism. In the chimeric mice, we observed an elimination of donor-reactive lymphocytes as well as permanent skin graft acceptance. We found a correlation between the initial chimerism rate, especially in the mononuclear cell populations, and graft survival. Based on our study, we can recommend well-selected cell populations expressing c-kit receptor that possibly facilitate the induction of mixed chimerism and immune tolerance. Therefore, our findings contribute to a better understanding of mixed chimerism and may promote its use in clinical practice.
Highlights
The phenomenon of mixed chimerism gives hope for the induction of specific immune tolerance
The rate and kinetics of chimerism depends on the type of transplanted mouse stem/progenitor cells
To identify the optimal stem/progenitor cell population for the induction of chimerism, we first compared the level and stability of mixed chimerism in the peripheral blood cells of three groups of mice transplanted with either lin-/Sca-1+/c-kit+ (G1), lin-/Sca-1+/c-kit+ (G2) or lin-/Sca-1-/c-kit+ (G3) cells over a long-term 26-week observation period (Figure 2)
Summary
The phenomenon of mixed chimerism gives hope for the induction of specific immune tolerance. Because the transplantation of hematopoietic cells has been known to induce tolerance to donor antigens for over half a century [6], bone marrow stem cells have attracted the interest of many scientists. These are cell populations enriched in hematopoietic stem/ progenitor cells: CD34+ cells in humans [4,7,8] and c-kit+ cells in mice [5]. Diverse cell populations have been tested as additions to unfractionated bone marrow to support tolerance induction
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