The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia

Abstract

The prophylactic use of T cell depletion (TCD) strategies for the prevention of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation remains widespread. Initial reports of high incidence of graft rejection after TCD BMT led to a move away from this approach but improved conditioning regimens have reduced this risk substantially. The use of TCD has also been associated with higher relapse risk post-BMT although the success of donor leukocyte infusion (DLI) as treatment for relapse has reduced this problem, especially in chronic myeloid leukaemia (CML). Currently the use of TCD BMT is increasing particularly due to the relative increase in BMT from non-related donors for whom TCD is the optimal GVHD prophylaxis. However, doubts remain over the long-term effect on the reconstituted immune system of recipients of TCD BMT, particularly in adult recipients. In this study we have undertaken a detailed sequential analysis in 23 patients who received allo-grafts from HLA-identical sibling donors after high-dose chemo/radiotherapy for acute or chronic leukaemia. Of these patients, 11 received non-manipulated grafts, five received 'partially TCD' (PTCD) and a further seven received 'fully TCD' (FTCD) bone marrow. T cell depletion was performed ex vivo by Campath-1M plus autologous serum as a source of complement. Partial TCD describes grafts with a T cell reduction of 1-2 log. Full TCD refers to grafts with a reduction of >2.5 log. The decision regarding the optimal degree of TCD was clinical and was based upon the perceived relative risk of relapse based upon the disease and remission status. All patients were monitored for up to 12 months post-BMT with regard to reconstitution of T and NK cell subsets. T cell depletion at either level was associated with a slower recovery of CD4 cells. This was most marked in the FTCD recipients and lasted throughout the period of study. CD8 cell recovery was also slower in the TCD recipients but this normalised throughout the 12 months post-BMT. The ratio of CD45RA+:CD45RO+ increased in all recipients after month 3. This suggests that a degree of extra-thymic T cell maturation can occur in recipients of allogeneic BMT. NK cell recovery was more rapid in the TCD recipients and these differences were maintained throughout the first year.

Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen

“…5,8 Phenotypic analysis of PBMC demonstrated that within 3-6 months various cell subpopulations recover and most return to normal levels within 12 months post allogeneic transplantation. 6,22,[25][26][27] Following both myeloablative and low intensity conditioning, our FACS analysis of PBMC is in accordance with data published previously, showing a decrease in the absolute number of CD4 + cells accompanied by an increase in CD8 + cells which led to an inverted CD4/CD8 cell ratio. 6,22,[25][26][27] Both regimens resulted in a long-lasting increase in activated cells carrying the HLA-DR cell surface marker in contrast to the number of HLA-DR + cells in normal PBMC.…”

Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis

“…20 We also expect enhanced immune reconstitution since this has been shown to be directly proportional to the number of T cells in the infused graft. 8 This method may also exploit antigen differences on normal tissues and leukaemia cells in that donor responses to recipient MHC and ubiquitous mHA are eliminated while conserving responses to lineage-restricted or even leukaemia-specific antigens. This would translate into a graft-mediated antileukaemia activity.…”

“…[4][5][6][7] So far, successful use of T cell depletion has required the establishment of an appropriate balance between the residual immune response of the recipient, which can be achieved by enhanced conditioning, and the adjustment of the T cell content of the donor bone marrow. 8,9 That T cells play an integral role in the mechanisms of graft rejection, GVHD and in GVL activity is no longer in doubt. What has proved to be more difficult has been the identification of specific subsets of cells involved in each of these activities.…”

Donor lymphocyte infusions in adult haploidentical transplant: a dose finding study

“…5 At the time we started the study, NK alloreactivity started to emerge as a major player in the GVL effect of the transplant, 6 which was confirmed later on 4 and we have incorporated these data from the start in choosing the donor. Since T-celldepleted transplants are 'per se' at a higher risk of relapse, 7 we thought that the other parameters upon which to play were T cell add-back and the type of growth factors used post-transplant.…”