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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2002-11-3516.
Submitted November 25, 2002
Accepted May 13, 2003
Selective depletion of donor allo-reactive T-cells without loss of anti-viral or anti-leukemic responses
Persis J Amrolia*, Giada Muccioli-Casadei, Eric Yvon, Helen Huls, Uluhan Sili, Eric D Wieder, Catherine Bollard, Helen E Heslop, Jeffrey J Molldrem, Cliona M Rooney, and Malcolm K Brenner
Department of Bone Marrow Transplantation, Great Ormond St Childrens Hospital, London, United Kingdom
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
Department of Bone Marrow Transplantation, MD Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: AmrolP1{at}gosh.nhs.uk.
Poor immune reconstitution after haplo-identical stem cell transplantation results in a high mortality from viral infections and relapse. One approach to overcome this problem is to selectively deplete the graft of allo-reactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient PBMC and this can result in GVHD. We have refined this approach using recipient EBV-transformed LCL as stimulators to activate donor allo-reactive T-cells. Our studies demonstrate that allo-depletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCL more consistently depleted in vitro allo-reactivity than stimulation with host PBMC, as assessed in primary MLR. Allo-depletion using this approach specifically abrogates cytotoxic T-cell responses against host LCL. In IFN- ELISPOT assays, anti-viral responses to adenovirus and CMV were preserved following allo-depletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T-cells is unaffected by allo-depletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the non-shared haplotype. Finally, we studied whether allo-depletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLAA2- PR1 tetramer analysis, we found that the frequency of T-cells recognising the PR1 epitope of proteinase 3 was not significantly different in allo-depleted and unmanipulated PBMC from transplanted patients with CML. Based on these data, we have embarked on a Phase 1 clinical trial of addback of allo-LCL depleted donor T-cells in the haploidentical setting.
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