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FL/G-CSF/AMD3100 Mobilized Hematopoietic Stem Cells Induce Mixed Chimerism with Nonmyeloablative Conditioning and Transplantation Tolerance without GVHD

H. Xu, Z. Zhu, D. Corbin, Y. Huang, S. Ildstad

Institute for Cellular Therapeutics, University of Louisville, Louisville, KY

Meeting: 2013 American Transplant Congress

Abstract number: 383

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Mobilized hematopoietic stem cells (HSC) now serve as a major source for transplantation. Better mobilizing approaches are clinically important. AMD3100, a CXCR4 competitive inhibitor, has been found to be a rapid mobilizing agent. We demonstrated that 5.0 mg/kg was the optimal dose of AMD3100 and mobilization peaked at 1 hour. For better mobilization, AMD3100 was co-administered (day 10) with FLT3-ligand (FL, day 1 to 10) and G-CSF (day 4 to 10). The 230.8-fold and 10.1-fold increase of lineage–/Sca-1+/c-kit+ HSC and CD8+/TCR– facilitating cells was detected when compared with AMD3100 treatment alone (P < 0.00001), respectively.

To determine the engraftment-potential of mobilized HSC from B6 (H-2b) mice with FL/G-CSF/AMD3100, MHC disparate BALB/c (H-2d) mice were lethally irradiated with 950 cGy total body irradiation (TBI) and reconstituted with varying doses of mobilized peripheral blood mononuclear cells (mPBMC) from of 10 × 106 to 1 × 106. All recipients expired by day 40 with manifestation of acute GVHD including weight loss, diarrhea, and hunched posture. When T cells in mPBMC were eliminated by sorting out ΑΒ-TCR+ and ΓΔ-TCR+ T cells, long-term survival and engraftment were achieved in the majority of recipients.

To evaluate whether outcomes correlated with the intensity of conditioning, recipients were nonmyeloablatively conditioned with anti-CD154 (day 0 and +2) and rapamycin (day 0 to +4) plus 100-300 cGy of TBI and transplanted with 2 x 106 mPBMC. 42.9%, 85.7%, and 100% mice engrafted at 1 month with 100, 200, and 300 cGy, respectively. Chimerism was durable and stable > 6 months and multilineage. Lymphocytes from mixed chimeras showed no response to both host- and donor-antigens, suggesting functional bi-direction T cell tolerance. Humoral tolerance was demonstrated as no antibodies were detected against donor. Most importantly, all engrafted mice were healthy without any GVHD. In mixed chimerism, the allo-activated T cells were deleted by negative selection in the thymus to balance both immune systems without triggering the GVHD. Moreover, we found that anti-CD154 co-stimulation blocking and rapamycin synergistically prevented GVHD.

In summary, FL/G-CSF/AMD3100 is an efficient synergistic treatment to maximally mobilize HSC. Durable engraftment and donor-specific tolerance can be achieved with mPBMC in a nonmyeloablative conditioning strategy without causing GVHD.

Ildstad, S.: Other, Regenerex, LLC, CEO.

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To cite this abstract in AMA style:

Xu H, Zhu Z, Corbin D, Huang Y, Ildstad S. FL/G-CSF/AMD3100 Mobilized Hematopoietic Stem Cells Induce Mixed Chimerism with Nonmyeloablative Conditioning and Transplantation Tolerance without GVHD [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/flg-csfamd3100-mobilized-hematopoietic-stem-cells-induce-mixed-chimerism-with-nonmyeloablative-conditioning-and-transplantation-tolerance-without-gvhd/. Accessed April 16, 2021.

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