Research in the Wall laboratory – Where hematopoiesis meets immunology

Hematopoietic stem cell transplant is the oldest form of stem cell therapy and is successfully used in the replacement of defective hematopoietic systems (aplastic anemia, sickle cell anemia, immunodeficiencies) and the treatment of leukemia and solid tumors.

Despite recent advances in hematopoietic stem cell transplant, reduced intensity transplant preparative regimen and use of haplo-identical grafts, there is still a great need for improvement at the pre- and post-transplant stages.

Our research projects target problems/situations at pre- and post-transplantation stages.

Impact of pre-transplant inflammation on the host hematopoietic stem cell susceptibility to the transplant preparative regimen
(pre-transplant) 

 

Patients who are inflamed in the immediate pre-transplant period (e.g. patients with hemophagocytic lymphohistiocytosis or recent infections) pose a challenge – often resulting in poor graft function, mixed chimerism or late graft failure post-transplant. It has been shown that inflammatory cytokines can affect hematopoietic stem cell fate and function. In this project we will study the effect of these inflammatory cytokines on hematopoietic stem cells and how this alters their susceptibility to the pre-transplant preparative regimen.. This will not only clarify the role inflammation plays in HSC biology but also lead to a change in pre-transplant preparative regimen for inflamed patients and ultimately any patient undergoing hematopoietic stem cell therapy.

Graft Engineering
(pre-transplant)

 

The graft (donor cells that are infused into the patient) doesn’t only consist of hematopoietic stem cells they actually are only a minority of the total cell product. There are many supporting mature immune cells like myeloid cells, T cells and B cells, some of which can cause adverse reactions in the patient – graft versus host disease, while other cells can help fight the left-over cancer cells. Therefore optimizing graft composition is of major interest to improve engraftment and immune recovery and prevent graft-versus-host disease. 

Role of myeloid derived suppressor cells in the graft and post-transplant
(pre- and post-transplant)  

 

Major complications in hematopoietic stem cell transplant include graft-versus-host disease (GVHD) and relapse of the underlying disease – both controlled by donor-derived immune reactivity against the host (GVHD) and/or the cancer (also known as graft-vs-leukemia (GVL)). Myeloid derived suppressor cells (MDSC) are a heterogeneous population of young myeloid cells with strong immunosuppressive features. These cells massively expand in the early post-transplant setting and are further expanded in cancer, autoimmunity and chronic infections. To date the role of MDSC and their downstream effect on immune cells has been underappreciated as an important checkpoint in the GVL/GVHD balance.

This project will measure MDSCs and other components of the immune system in a cohort of patients undergoing hematopoietic stem cell transplant. We will study the dynamics of activation of all the early cellular elements in patients with and without GVHD/relapse – identifying important interactions that set the stage for GVHD/GVL.  In addition, we will develop an in vitro differentiation strategy, starting from human hematopoietic stem/progenitor cells, to identify conditions that drive early myeloid cells to become MDSC and optimize expansion strategies.

Immune Tolerance in Transplant: Learning from Hematopoietic Mixed Chimeras
(post-transplant)

 

Allogeneic hematopoietic stem cell transplant is usually performed to completely replace the recipient’s (defective) cells with donor’s (healthy) hematopoietic cells – full donor chimerism. However, sometimes transplant results in mixed chimerism, meaning the hematopoietic system consists of both donor and recipient cells. How this state of tolerance is created is still unclear. In this project, we will study patients with long-term mixed chimerism and characterize their hematopoietic system by changes in blood types and the immune system in this state of tolerance. A better understanding of this state of tolerance will help in the safe and effective design of clinical trials for a combined solid organ transplant and hematopoietic stem cell transplant. This will not only lead to improved graft survival, without the need of immune suppressive medication but will also increase the donor options for children. 

Virus Specific Cytotoxic T-cells as a potential therapy against viral infections post-transplant
(post-transplant)

 

Viral infections are a major cause of morbidity and mortality after allogeneic-hematopoietic stem cell transplant as it takes time for the immune system to fully recover.  Although incidence and severity of viral infections/reactivations can be lowered by prophylactic and therapeutic antiviral chemotherapy, the efficacy of these treatments are limited and are frequently associated with significant side effects. Previous studies have shown that sufficient T-cell immunity is essential for the control and prevention of viral reactivations and newly occurring infections. Infusion of virus-specific T-cells targeting CMV, EBV and/or others can significantly reduce morbidity and mortality in patients undergoing allogeneic-hematopoietic stem cell transplant. In this project, we will explore the potential of generating clinical grade virus–specific cytotoxic T cells for prophylactic and/or therapeutic treatment of viral infection/reactivation after allogeneic-hematopoietic stem cell transplant.