Abstract:
Progress in understanding the human haemopoietic system has depended on suitable models of normal and malignant haemopoiesis, particularly in vivo models. Further opportunities to develop models have arisen with the availability of the severe combined immunodeficient (SCID) mouse.
Human umbilical cord blood is rich in progenitors and may engraft more readily than adult tissues. Cord blood was injected iv into sublethally irradiated SCID mice, with 5/10 donors engrafting 3 – 29% human cells in murine bone marrow (BM), as demonstrated by immunofluorescence, fluorescence in situ hybridisation, and clonogenic growth of human cells. However, in total, only 8/60 mice engrafted and transplantation to other mice failed, limiting the usefulness of this model.
Engraftment of acute lymphoblastic leukaemia (ALL) was both frequent and reliable. 7/15 cases engrafted and disseminated in SCID mice, in many cases resembling the human clinical disease. Passage of xenograft ALL to further mice was successful in many cases, with maintenance of immunophenotype and karyotype, but reduced mouse survival with successive passage. Lower doses of preparatory radiation were associated with longer survival times of mice. The minimum number of ALL cells required for engraftment varied from 2x103 - 2x105 cells for two cases.
In contrast, only 1/14 cases of AML engrafted, although co-engraftment with cord blood was successful for two AML cases. A small number of cases of other haemopoietic malignancies failed to engraft with the exception of ALL arising as blast crisis of chronic myeloid leukaemia (CML).
The human ALL model was used to test novel therapies following initial assessment of a standard cytotoxic agent. Vincristine suppressed human xenograft ALL and the model was sensitive to variations in dose and schedule. Interleukin-4 (IL-4) was inhibitory for primary ALL in vitro. In the SCID mouse model, IL-4 delayed the appearance of circulating leukaemia cells and improved survival. Antisense bcr/abl oligodeoxynucleotide inhibition of leukaemia was also investigated. Antisense was inhibitory for some CML cell lines in vitro, but with little evidence of specificity. In the SCID mouse model, antisense appeared to suppress circulating blast crisis CML cells but without a clear effect on survival.
These SCID mouse models allowed investigation of aspects of the biology of normal and malignant haemopoiesis, as well as the assessment and development of novel therapies. However, mice with more severe immune defects, such as the NOD-SCID mouse, may prove more suited to many of these applications.