Introduction and aim
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.
Materials and methods
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.
Summary of results
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).
Conclusions
For the first time, by careful guidance of reconstitution, without any need for myeloablation, one can achieve donor chimerism and tolerance after depletion.
