T cells and innate lymphoid cells (ILCs) in cutaneous graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important
modality in the treatment of hematologic malignancies and bone marrow failure
syndromes. While curative in many, allogeneic HSCT is often complicated by
graft versus host disease (GvHD), an alloimmune response of donor immune cells
against healthy recipient*s tissues including skin, liver, lungs and gut with
high morbidity and mortality.

GvHD continues to be the main cause of non-relapse mortality and morbidity
developing in more than 50% of patients after HSCT. GvHD is primarily a donor T
cell-mediated syndrome whereby T cells derived from the stem cell graft elicit
an immune response, resulting in host tissue damage. Despite its high
prevalence and its considerable morbidity and mortality, the biology of GvHD
remains incompletely understood.

At the AMC, two groups are studying GvHD immunology. Drs Tiago R. Matos
(Dermatology department) is an immunologist interested in T cell biology. He
has set up the T cell receptor (TCR) CDR3-specific deep-sequencing technique,
to study the dynamics and function of T cell clones in health and disease, in
particular in GvHD. The group of Dr Mette Hazenberg (Hematology department) has
an interest in innate lymphoid cells (ILCs), a recently identified group of
cells that are important in inflammatory diseases. They were the first to
demonstrate the importance of ILC in GvHD of the gut.

With their joined interest in GvHD immunology of the skin Drs Matos and
Hazenberg decided to join forces. They will study the immune pathophysiology of
cutaneous GvHD longitudinally, using blood and skin biopsies from patients with
active GvHD and after treatment, when symptoms have resolved.

The overall aim of the study is to improve our understanding of the role of T
cells and ILCs in cutaneous GvHD, to lay the foundation for the development of
better therapies to treat cutaneous GvHD.

1. T cells in GvHD
The dominant cell population in tissues affected by GvHD is the T cell
population, in particular CD4 and CD8 T cells that produce interferon (IFN)
gamma, interleukin (IL)-17 and IL-22. In addition, the lack of immuneregulatory
T cells (Tregs), that have a dampening effect on the immune response, is
important in GvHD pathophysiology. To make things more complicated, it has been
demonstrated that T cells are plastic: Tregs can become effector T cells, and
activated T cells can become Tregs. Recently, it has become possible to study
the plasticity of T cells by tracking the fate of T cell clones, using the TCR
CDR3-specific deep-sequencing technique. With this technology, we will track
the fate of T cell clones that are present in the skin and blood of GvHD
patients during active disease and after resolution of symptoms.

2. ILCs in GvHD of the skin
ILCs are the innate equivalents of T cells. In the past years we have presented
data suggesting that IL-22 producing ILCs are important in protecting the gut
from GvHD. However, IL-22 producing ILC can also have detrimental effects, as
we have shown in the setting of the autoimmune skin disease psoriasis. In the
present study we aim to study the contribution of ILCs in GvHD pathophysiology,
by analyzing the phenotype and function of ILCs in skin and blood of patients
during activate GvHD and after resolution of symptoms.

As T cells and ILCs produce the same cytokines (IFNg, IL-17 and IL-22), results
will be combined and compared to study the interaction of both immune
populations.

This is a single center, single arm, observational trial.

Risks associated with skin biopsy are bleeding and infection, both of which
neglectable because of the small size of the biopsy. At both time points blood
will be drawn. Vena puncture can result in a hematoma at the site of puncture.
We hope that this research unveils the specific pathogenic subsets of T cells
and ILCs that promote GvHD. Such knowledge is essential for future studies,
which then can monitor those cell subsets in patients that received allogenic
stem cell transplantation as a potential early biomarker of GvHD, and allow the
development of better therapies to treat cutaneous GvHD.