Ex vivo and in vivo T-cell depletion in allogeneic transplantation: towards less or non-cytotoxic conditioning regimens

ABSTRACT

Introduction

Although tremendous progress has been made since the introduction of allogeneic hematopoietic stem cell transplantation (HSCT) decades ago, there are still many obstacles to overcome. A major obstacle is the presence of T-lymphocytes in the recipient and in the donor. Recipient-derived T-lymphocytes not eliminated by the conditioning regimen are a major barrier and can lead to mixed chimerism or to complete rejection of the graft. Donor-derived T-lymphocytes can induce severe acute and chronic Graft-versus-Host Disease (GvHD).

Areas covered

Currently published strategies for in vivo depletion of recipient-derived T-lymphocytes are discussed including the increase of the intensity of the conditioning regimen, the addition of anti-thymocyte globulin (ATG) or the anti-CD52 monoclonal antibody Campath. For the depletion or tolerization of the donor-derived T-lymphocytes, ex vivo-T-cell depletion methods, such as positive selection of CD34+ stem cells, negative depletion of CD3+ or TcRαβ+ T-lymphocytes or the use of post-transplant cyclophosphamide (PTCy) have been developed.

Expert Commentary

All these currently used approaches have their disadvantages and new approaches should be investigated. In this review, we discuss current and propose new possible strategies to overcome the HLA barrier by using more specific T-cell directed therapies and/or by the combinations of current methods.

KEYWORDS:

• Hematopoietic stem cell transplantation (HCT)
• Graft-versus-host disease
• Host-versus-graft reaction
• rejection
• conditioning regimen
• haploidentical transplantation
• ex vivo T-cell depletion
• posttransplant cyclophosphamide (PTCy)
• alloreactivity

Acknowledgments

The work was supported by the Elternverein und Stiftung für krebkranke Kinder e.V. Tübingen.

Article highlights

• Ex vivo depletion of donor T-lymphocytes reliably prevents severe Graft-versus-Host Disease

• Post-transplant Cyclophosphamide (PTCy) can tolerize donor T-lymphocytes in T-replete stem cell transplantation

• PTCy might also tolerize residual alloreactive recipients’ T-lymphocytes

• A combination of ex vivo T-cell depletion of donor T-cells and tolerization of recipients’ T-cells with PTCy can facilitate engraftment with less aggressive conditioning regimens

• The combination of ex vivo T-cell depletion with PTCy and additional polyclonal or monoclonal antibodies might allow less or even non-toxic conditioning regimens for non-malignant diseases.

Declaration of interest

R Handgretinger is the co-inventor and co-patent holder of the TcRαβ depletion technology together with the Miltenyi Biotec company. P Lang has received grant support from Miltenyi Biotec. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work was supported by the Elternverein und Stiftung für krebkranke Kinder e.V. Tübingen.