PMID- 12064093
OWN - NLM
STAT- MEDLINE
DCOM- 20021122
LR  - 20091111
IS  - 0907-8916 (Print)
IS  - 0907-8916 (Linking)
VI  - 49
IP  - 2
DP  - 2002 May
TI  - Alloreactivity and the predictive value of anti-recipient specific interleukin 2 
      producing helper T lymphocyte precursor frequencies for alloreactivity after bone 
      marrow transplantation.
PG  - 89-108
AB  - Allogeneic bone marrow transplantation (BMT) is a treatment modality with the 
      potential of curing otherwise lethal diseases. The predominant indications for 
      BMT are haematological malignancies. In BMT alloreactivity plays a pivotal role 
      for the outcome. Graft-versus-host disease (GvHD) and graft-versus-leukaemia 
      (GvL) are correlated manifestations of alloreactivity. Severe GvHD is one of the 
      main causes of morbidity and mortality post-BMT. In the absence of GvL the risk 
      of relapse is high. The main effector cells are T lymphocytes. Donor leukocyte 
      infusion (DLI) for treatment of leukaemic relapse after BMT can induce durable 
      remissions. DLI causes GvHD in the majority of the responding patients. However, 
      a GvL effect may be present without evidence of GvHD and vise versa. The 
      importance of alloreactivity for the treatment outcome prompted the interest for 
      a predictive test of alloreactivity. Interleukin 2 (IL-2) producing helper T 
      lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis 
      (LDA) in the graft-versus-host direction were explored. The HTLp assay was 
      optimized and the sources of error minimized to ensure sensitive and reproducible 
      results. The IL-2 dependent cell line, CTLL-2 was optimized to detect 0.6 pg 
      IL-2. UV-B irradiation of the cells was demonstrated to effectively terminate 
      proliferation of the responder cells and thus allow IL-2 to be detected in the 
      whole culture volume. The design of the assay was explored by Monte Carlo 
      simulations resulting in a design yielding frequencies with a coefficient of 
      variation of 20% in the range of 1:20,000-1:1,000,000. The influence of 
      autoreactivity of the donor and recipient cells was minimized as well as the risk 
      of the stimulator cells producing IL-2. The HTLp frequencies correlated with the 
      degree of human leukocyte antigen (HLA) disparity and the assays were able to 
      detect minor histocompatibility antigen mismatches. The HTLp frequencies of 28 
      HLA-identical sibling BMT pairs and 20 HLA-matched unrelated and partially 
      HLA-matched related BMT pairs were determined. HTLp frequencies from the 
      HLA-identical sibling BMT pairs had a median of 1:557,362 (range 1:9.511 to < 
      1:2,500,000). The HTLp frequencies from the HLA-matched unrelated and partially 
      HLA-matched related BMT pairs had a median of 1:88,110 (range 1:4.139-1:736,123). 
      Analysis of the HLA-identical sibling BMT pairs in a high and a low HTLp 
      frequency group above and below 1:500,000 showed a trend towards a higher risk of 
      acute GvHD > or = grade II and a significantly higher risk of chronic GvHD in the 
      high HTLp frequency group. This group had a significantly lower risk of relapse 
      as well as a significantly better overall survival and leukaemia free survival. 
      The HLA-matched unrelated and partially HLA-matched related BMT pairs were split 
      evenly in a high and a low HTLp frequency group above and below 1:90,000. There 
      was a significantly higher risk of acute GvHD > or = grade II and a trend towards 
      a higher treatment related mortality (TRM) in the high HTLp frequency group. 
      There were no differences in chronic GvHD, risk of relapse, overall survival and 
      leukaemia free survival. Analyzing all 48 patients the risk of acute GvHD > or = 
      grade II and TRM was significantly higher with HTLp frequencies > 1:100,000 and 
      there was a trend towards a higher risk of relapse with low HTLp frequencies < 
      1:400,000. Patients in the intermediate HTLp frequency group 1:100,000-1:400,000 
      had a trend towards improved survival. The HTLp frequency seems to detect 
      clinically significant differences in alloreactivity, that can be useful in donor 
      selection, graft-engineering, T cell add-back and the pharmacological 
      immunosuppression used after BMT.
FAU - Russell, Charlotte Astrid
AU  - Russell CA
AD  - Department of Haematology, H:S Rigshospitalet, Copenhagen.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - Denmark
TA  - Dan Med Bull
JT  - Danish medical bulletin
JID - 0066040
RN  - 0 (HLA Antigens)
RN  - 0 (Interleukin-2)
SB  - IM
MH  - Bone Marrow Transplantation/*immunology
MH  - Graft Rejection/immunology
MH  - Graft vs Host Disease/diagnosis/immunology
MH  - Graft vs Leukemia Effect/immunology
MH  - HLA Antigens/analysis
MH  - Histocompatibility
MH  - Humans
MH  - Immunologic Tests
MH  - Interleukin-2/*metabolism
MH  - T-Lymphocytes, Helper-Inducer/*immunology/metabolism
MH  - Transplantation, Homologous/immunology
RF  - 228
EDAT- 2002/06/18 10:00
MHDA- 2002/11/26 04:00
CRDT- 2002/06/18 10:00
PHST- 2002/06/18 10:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/06/18 10:00 [entrez]
PST - ppublish
SO  - Dan Med Bull. 2002 May;49(2):89-108.