PubMed · 1912957
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J N Frame. 1991. Multicenter trials versus observational databases.. https://pubmed.ncbi.nlm.nih.gov/1912957/
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BACKGROUND: In this large, two-center study, 260 cytotoxic T lymphocyte precursor (CTLp) frequency assays, performed to assess patient-donor compatibility, were analyzed in relation to the degree of HLA matching. METHODS: While the tissue-typing techniques used at the Royal Postgraduate Medical School (RPMS) and Anthony Nolan Bone Marrow Trust (ANBMT) differ, the results of the analyses on the two sites are analogous, with high CTLp frequencies (>1:100,000) in 42% and 41% of recipient-donor pairs, respectively. RESULTS: Recipient-donor combinations with class I mismatches and class II identity were associated with high CTLp frequencies (collectively 83% vs. 17% low CTLp). This correlation was not as strong in pairs where class II mismatches were demonstrated (61% high vs. 39% low). Despite using different matching procedures, the RPMS and ANBMT both show that 32% of the "perfectly" matched pairs (i.e., where no mismatch was detected by any of the techniques used here) had high frequencies of recipient-specific CTLp. CONCLUSIONS: The failure of conventional methods to identify such a level of histoincompatibilities indicates that the CTLp assay has an important role in the selection of unrelated donors for bone marrow transplantation.
Many chromosomal translocations involved in leukemia have been defined at the molecular level in recent years. In addition to advancing the understanding of pathological mechanisms underlying the transformation process, the cloning and sequencing of the genes altered by the translocations have provided new tools for diagnosis and monitoring of patients. In particular, the polymerase chain reaction (PCR) method yields sensitive and accurate diagnostic and prognostic information. Minimal residual disease (MRD) is not clearly defined. In ALL we define MRD as fewer than 5% blast cells in the bone marrow by conventional cytology and proof of leukemic cells with more sensitive methods. The techniques for detecting MRD are imaging for detection of single leukemic cells in the blood, bone marrow, or other tissues by means of immunocytology or PCR/RT-PCR. Highly sensitive PCR, immunocytology, FACS analysis, or conventional cytology are important tools to use in the process of deciding on appropriate therapy. Detection limits at present are 10(-2) for cytology and FISH, up to 10(-4) for immunological procedures, and 10(-5) to 10(-6) for PCR. But multiple methods also imply the possibility of mistakes (e.g., PCR). The question must be raised what method should be decisive in assessing MRD for evaluating autologous peripheral blood stem cells (PBSC) or autologous bone marrow transplants? Prospective studies will have to answer the question whether MRD should be treated or not and whether purging of bone marrow or PBSC is useful or damaging. When applied, should a positive or a negative immunopurging or a chemotherapeutic purging be used? MRD refers to the organism of the patient as well as to the peripheral blood stem cells and autologous bone marrow that had been taken before myeloablative therapy and kept for retransfusion.
We have postulated that the donor leukocyte microchimerism plays a seminal role in the acceptance of allografts by inducing and perpetuating variable degree of donor-specific nonreactivity in long-surviving organ recipients. Limited information is available, however, concerning the phenotype and function of these chimeric cells in humans. The unequivocal presence of donor dendritic cells (DCs), a prominent lineage in the microchimerism observed in rodents and clinical organ recipients, was difficult to demonstrate in bone marrow (BM)-augmented organ transplant recipients. This enigma was resolved by the recent description of a method for propagating circulating human DCs from their progenitors by culture in a medium enriched with granulocyte-macrophage colony-stimulating factor and interleukin 4, a condition known to inhibit outgrowth of monocytes, thus providing a selective growth advantage to committed progenitors of the myeloid lineage. Cells from BM-augmented organ recipients and normal control subjects harvested from 12- to 14-day cultures exhibited dendritic morphology and potent allostimulatory capacity. Using appropriate primers, the presence of donor DNA was verified by polymerase chain reaction within the lineage(null)/class II(bright) sorted DC. Phenotypic analysis of cultured DCs from BM-augmented patients, unlike that of controls, exhibited a marked down-regulation of B7-1 (CD80) while retaining normal levels of expression of B7-2 (CD86) cell surface molecules. The presence of donor DNA was also confirmed by polymerase chain reaction in individually sorted lineage+ (T, B, and NK) cells and macrophages, suggesting that the chimerism in BM-augmented patients is multilineage. The presence of progenitors of donor DCs in the peripheral blood of BM-augmented patients further substantiates the already convincing evidence of stem cell engraftment.