This collection of review articles on hematopoietic stem cell transplantation (HSCT)
has been compiled by enthusiastic post-graduate students within the Marie Curie Initial
Training Network CELLEUROPE. It starts with two reviews of current research with a
historical perspective and focus on either animal or human HSCT studies.
Boieri et al. summarize the importance of early animal experiments from the 1950's
including graft-vs.-host disease (GvHD) a major complication of HSCT, initially termed
“runt disease.” The article focuses on the contribution of animal experiments to the
understanding of the pathophysiology of acute and chronic GvHD and the development
of therapies to overcome these complications. It ends with a discussion of general
advantages and limitations of animal models for studying GvHD.
The historic milestones of HSCT in man are reviewed by Juric et al. They describe
the development of conditioning therapies enabling engraftment of HSC. The pivotal
role of human leukocyte antigen (HLA) typing technologies for the introduction and
continuous improvement of HSCT is explained. The shift from serological to molecular
methods is discussed in view of their importance for the utilization of matched unrelated
donors. Further parameters affecting HSCT outcome are introduced focusing on stem
cell sources ranging from bone marrow to peripheral HSC and cord blood. The article
closes with an outlook on new developments, such as the adoptive transfer of T cells
engineered to express chimeric antigen receptors (CARs) directed against antigens
present on leukemic cells.
Ghimire et al. discuss in detail the pathophysiology of GvHD explaining initiation
and course of both the acute and chronic forms and introducing new strategies to limit
these complications. Despite these efforts, especially chronic GvHD remains a major
challenge that warrants further research.
The risk to elicit GvHD by transplantation of allogeneic T cells is balanced by their
potential for profound graft-vs.-leukemia (GvL) effects, giving rise to curative therapies
for malignancies. Dickinson et al. summarize clinical observations and experimental
results demonstrating that allogeneic T cells in the graft reduce the risk of relapse
of malignancy after HSCT. They describe the development of donor lymphocyte infusion
(DLI) as a means to treat relapse. In addition, newer strategies are explained including
the infusion of allogeneic mismatched natural killer (NK) cells or tumor antigen-specific
The reconstitution of the immune system after HSCT is reviewed by Ogonek et al.. It
is of the utmost importance for the success of HSCT, that the various immune cell
subsets recover and regain function in a timely manner. Neutrophils are the first
cells that usually reappear within the first month after the conditioning therapy.
They are followed in the first 3 months by NK cells and then by T cells. B cell recovery
takes longer and may need up to 2 years post-HSCT. The reconstitution of regulatory
T cells is explained focusing on factors which influence reconstitution, such as immunosuppressive
treatment. Finally, the reconstitution of virus-specific T cells is reviewed in view
of the clinical importance of these cells for avoiding complications such as CMV reactivation.
Biomarkers have gained much attention as they may predict the occurrence of GvHD and
allow for risk-adapted treatment. Juric et al. review the recent developments and
start with a discussion of cellular biomarkers, such as CD19+CD21low B cells that
are promising in predicting chronic GvHD. Besides cells, serum molecules have been
reported to predict GvHD. In addition to proteins, miRNAs are potentially promising
biomarkers for GvHD. Moreover, recent developments to identify biomarkers in urine
by proteomic approaches are presented. Juric et al. close by discussing the challenge
to validate and integrate the great variety of biomarkers that have been suggested
during the last few years.
Gam et al. discuss the genetic associations of HSCT outcome focusing on non-histocompatibility
genes and three specific examples. Firstly, it is discussed how polymorphisms of FOXP3
and FOXP3-regulating microRNAs affect the risk of GvHD. The miR-155 and miR-146a regulatory
network, their polymorphisms and role after HSCT is outlined as a second example.
Polymorphisms of the MICA gene, which encodes a ligand of the activating NK cell receptor
NKG2D, are introduced as a third example. Furthermore, mRNA and miRNA expression profiling
studies aiming at the identification of HSCT associated risks are summarized. The
review ends with a discussion of the few genome wide association studies, which have
been performed so far to elucidate the role mainly of non-HLA polymorphisms in controlling
the outcome of HSCT.
The final review by Reis et al. outlines recent developments in cellular immunotherapies
for HSCT-associated complications. These include the transfer of mesenchymal stromal
cells (MSCs) or MSC-derived extracellular vesicles to treat GvHD. Further complications
are infections occurring in the immunocompromised patients. In recent years, strategies
to employ anti-virus-specific T cells in the therapy of viral infections have been
developed. Relapse is another outcome that can be targeted by cellular immunotherapies,
e.g., with CAR T cells and in this chapter the challenges of these new and fascinating
therapeutic strategies is discussed.
This collection of articles is dedicated to Professor Bent Rolstad (1947-2016), an
enthusiastic and committed supervisor of two of the project's post-graduate students
and Professor Jon van Rood (1926-2017), who was encouraging and supportive to the
students in writing and revising the articles.
RD drafted the manuscript, which AD, HG, and EH revised. All authors approved the
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.