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T-cell depletion as a route to transplantation tolerance

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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.

release  1
pubblicata il  28 settembre 2012 
da Giovanni Piotti
(Dipartimento di clinica medica, nefrologia e scienze della prevenzione - Università di Parma, Italia. Sir William Dunn School of Pathology, Oxford University, England. ACKNOWLEDGMENTS: Prof. Herman Waldmann and Prof. Stephen Cobbold for supervision; Italian Society of Nephrology for financial support (Bando di ricerca SIN 2011).)
Parole chiave: Tolleranza trapiantologica, trapianto renale
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Realizzazione: Tesi S.p.A.

Per assistenza contattare: Claudia Ingrassia, Tesi S.p.A.
0172 476301 — claudia.ingrassia@gruppotesi.com