Organ transplantation is the optimal treatment for several end-stage organ diseases.
Long-term outcomes are however unsatisfactory due to the side effects of maintenance immunosuppressants.
Transplantation tolerance is clinically desirable, and possible in mice by blocking key T-cell co-receptors and co-stimulatory molecules, but not by ablating T-cells [1].
A major barrier to transplantation tolerance after lymphocyte ablation is reconstitution by homeostatic expansion of tolerant-resistant memory T-cells [2].
I investigated how the lymphocyte reconstitution following T-cell depletion might be guided to favour regulation and tolerance.
Mice strains. Mismatched skin and marrow donors: H-2b mice.
Recipients: human-CD52 expressing transgenic H-2k mice [3].
Monoclonal antibodies and immunosuppressants.
Campath: anti-human CD52 Ab to deplete T-cells.
Anti-CD4 and anti-CD8 Ab to block T-cells co-receptors.
Anti-IL7R: anti-IL-7 receptor blocking Ab [4].
Anti-CD40L Ab to block a key co-stimulatory molecule.
Rapamycin: mTOR inhibitor widely used in clinical practice.
T-cell depletion is insufficient to induce tolerance (Fig. 1 and 2).
A short treatment with an αIL-7R Ab and Rapa can guide T-cell reconstitution to regulation and tolerance (Fig. 3 and 4).
Infusing donor marrow in advance of the tissue transplant, under the cover of a protocol built on T-cell depletion, establishes chimerism and induces transplantation tolerance (Fig. 5 and 6).
For the first time, by careful guidance of reconstitution, without any need for myeloablation, one can achieve donor chimerism and tolerance after depletion.
[1] Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL, Cendales LK, Tadaki DK, Harlan DM, Swanson SJ. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).
[2] Wu Z, Bensinger SJ, Zhang J, Chen C, Yuan X, Huang X, Markmann JF, Kassaee A, Rosengard BR, Hancock WW, Sayegh MH, Turka LA. Homeostatic proliferation is a barrier to transplantation tolerance.
[3] Gilliland LK, Walsh LA, Frewin MR, Wise MP, Tone M, Hale G, Kioussis D, Waldmann H. Elimination of the immunogenicity of therapeutic antibodies.
[4] Sudo T, Nishikawa S, Ohno N, Akiyama N, Tamakoshi M, Yoshida H, Nishikawa S. Expression and function of the interleukin 7 receptor in murine lymphocytes.
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