Novel therapeutics for the treatment of graft-versus-host disease

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.     

Novel approaches to treatment of sickle cell anaemia

Sickle cell anaemia, a chronic and often debilitating disease, results from homozygosity for a single amino acid substitution in the β-globin subunit of the haemoglobin molecule. Sickle haemoglobin (HbS), the product of this mutation, polymerises when deoxygenated, thus damaging the red blood cell and causing vaso-occlusive complications and haemolytic anaemia. Most cases of sickle cell anaemia are found in Africa. Until recently, treatment was directed at the management of disease complications. Patients with central nervous system events undergo exchange transfusions followed by chronic transfusion programmes. Patients with painful episodes, which result in many days missed from work and school are treated with narcotics and aggressive hydration. Novel therapy for sickle cell anaemia is designed to prevent complications through targeting disease mechanisms. Hydroxyurea is given to severely affected sickle cell anaemia patients in an attempt to prevent painful episodes, reduce hospital days, improve the patients’ overall quality of life, and perhaps to prevent or provide some degree of end-organ damage stabilisation. Other novel therapies, such as bone marrow transplantation and gene therapy, pursue a cure. For these novel therapies to be effective on a global basis they must be amenable to underdeveloped and poorer countries of the world.