Kate Cwynarski

CYTOMEGALOVIRUS SEROPOSITIVITY ADVERSELY INFLUENCES OUTCOME AFTER T-DEPLETED UNRELATED DONOR TRANSPLANT IN PATIENTS WITH CHRONIC MYELOID LEUKAEMIA: THE CASE FOR TAILORED GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T‐cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5u2003years for all patients was 52·6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14·5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV‐negative patients survival at 5u2003years was 60% vs. 42% in CMV‐positive patients (Pu2003=u20030·006). The use of TCD was associated with an increased risk of relapse (62% probability at 5u2003years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV‐seronegative recipients of MUD allografts, but in CMV‐seropositive patients this approach is associated with an increased non‐relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.

Location of major histocompatibility complex class II molecules in rafts on dendritic cells enhances the efficiency of T-cell activation and proliferation.

The existence of major histocompatibility complex (MHC) class II molecules in lipid rafts has been described in dendritic cells (DC); however, the importance of rafts in T‐cell activation has not been clarified. In this study, the distribution of the lipid raft components (CD59 and GM1 ganglioside) in human monocyte‐derived DC was investigated. DC had an even distribution of these components at the cell surface. In addition, raft‐associated GM1 ganglioside colocalized with cross‐linked MHC class II. This implies coaggregation of raft components with these MHC molecules, which may be important in the interaction between T cells and antigen‐presenting cells. In studies carried out to investigate the effect of the DCu2003:u2003T‐cell interaction on raft distribution, we found a clustering of the lipid raft component CD59 on DC at the synaptic interface, with associated activation of the interacting T cell. In an antigen‐specific response between DC and CD4+ T‐cell clones, disruption of lipid rafts resulted in inhibition of both CD59 clustering and T‐cell activation. This was most pronounced when limiting amounts of cognate peptide were used. Together, these data demonstrate the association of MHC class II with lipid rafts during DCu2003:u2003T‐cell interaction and suggest an important role for DC lipid rafts in T‐cell activation.

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia : association with leukaemic relapse and treatment with donor lymphocyte infusions

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD. Bone Marrow Transplantation (2001) 28, 581–586.