Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses

Persis J. Amrolia, Giada Muccioli-Casadei, Eric Yvon, Helen Huls, Uluhan Sili, Eric Wieder, Catherine Bollard, Helen E. Heslop, Jeffrey J. Molldrem, Cliona M. Rooney, Malcolm K. Brenner

Research output: Contribution to journalArticle

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Abstract

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 alloreactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient peripheral blood mononuclear cells (PBMCs), and this can result in graft versus host disease (GVHD). We have refined this approach using recipient Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as stimulators to activate donor alloreactive T cells. Our studies demonstrate that allodepletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCLs more consistently depleted in vitro alloreactivity than stimulation with host PBMCs, as assessed in primary mixed lymphocyte reactions (MLRs). Allodepletion using this approach specifically abrogates cytotoxic T-cell responses against host LCLs. In interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assays, antiviral responses to adenovirus and cytomegalovirus (CMV) were preserved following allodepletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T cells is unaffected by allodepletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the nonshared haplotype. Finally, we studied whether allodepletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLA-A2-PR1 tetramer analysis, we found that the frequency of T cells recognizing the PR1 epitope of proteinase 3 was not significantly different in allodepleted and unmanipulated PBMCs from patients with chronic myeloid leukemia (CML) undergoing transplantation. Based on these data, we have embarked on a phase 1 clinical trial of addback of allo-LCL-depleted donor T cells in the haplo-identical setting.

Original languageEnglish
Pages (from-to)2292-2299
Number of pages8
JournalBlood
Volume102
Issue number6
DOIs
StatePublished - Sep 15 2003
Externally publishedYes

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T-cells
Antiviral Agents
T-Lymphocytes
Human Herpesvirus 4
Viruses
HLA-A2 Antigen
Immunotoxins
Blood Cells
Blood
Tissue Donors
Cytomegalovirus
Grafts
Cell Line
Myeloblastin
Enzyme-Linked Immunospot Assay
Transformed Cell Line
Clinical Trials, Phase I
Mixed Lymphocyte Culture Test
Lymphocytes
Stem Cell Transplantation

ASJC Scopus subject areas

  • Hematology

Cite this

Amrolia, P. J., Muccioli-Casadei, G., Yvon, E., Huls, H., Sili, U., Wieder, E., ... Brenner, M. K. (2003). Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood, 102(6), 2292-2299. https://doi.org/10.1182/blood-2002-11-3516

Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. / Amrolia, Persis J.; Muccioli-Casadei, Giada; Yvon, Eric; Huls, Helen; Sili, Uluhan; Wieder, Eric; Bollard, Catherine; Heslop, Helen E.; Molldrem, Jeffrey J.; Rooney, Cliona M.; Brenner, Malcolm K.

In: Blood, Vol. 102, No. 6, 15.09.2003, p. 2292-2299.

Research output: Contribution to journalArticle

Amrolia, PJ, Muccioli-Casadei, G, Yvon, E, Huls, H, Sili, U, Wieder, E, Bollard, C, Heslop, HE, Molldrem, JJ, Rooney, CM & Brenner, MK 2003, 'Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses', Blood, vol. 102, no. 6, pp. 2292-2299. https://doi.org/10.1182/blood-2002-11-3516
Amrolia, Persis J. ; Muccioli-Casadei, Giada ; Yvon, Eric ; Huls, Helen ; Sili, Uluhan ; Wieder, Eric ; Bollard, Catherine ; Heslop, Helen E. ; Molldrem, Jeffrey J. ; Rooney, Cliona M. ; Brenner, Malcolm K. / Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. In: Blood. 2003 ; Vol. 102, No. 6. pp. 2292-2299.
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abstract = "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 alloreactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient peripheral blood mononuclear cells (PBMCs), and this can result in graft versus host disease (GVHD). We have refined this approach using recipient Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as stimulators to activate donor alloreactive T cells. Our studies demonstrate that allodepletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCLs more consistently depleted in vitro alloreactivity than stimulation with host PBMCs, as assessed in primary mixed lymphocyte reactions (MLRs). Allodepletion using this approach specifically abrogates cytotoxic T-cell responses against host LCLs. In interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assays, antiviral responses to adenovirus and cytomegalovirus (CMV) were preserved following allodepletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T cells is unaffected by allodepletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the nonshared haplotype. Finally, we studied whether allodepletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLA-A2-PR1 tetramer analysis, we found that the frequency of T cells recognizing the PR1 epitope of proteinase 3 was not significantly different in allodepleted and unmanipulated PBMCs from patients with chronic myeloid leukemia (CML) undergoing transplantation. Based on these data, we have embarked on a phase 1 clinical trial of addback of allo-LCL-depleted donor T cells in the haplo-identical setting.",
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