Fertility after homologous prepubertal testis transplantation in the dog.

Canine models of hereditary human diseases are widely used throughout the biomedical community, particularly when no suitable rodent model exists. In several models, the homozygote dogs die prior to puberty, or have substantially reduced fertility. Prepubertal transplantation of the testes was used to propagate the genotype of a mutant dog that would not otherwise have survived until puberty. The transplant recipient remained fertile 7 years postoperatively. To begin determining the factors necessary for successful function in testis transplants, prepubertal dogs that were dog leukocyte antigen (DLA) identical and disparate were examined for fertility and compared to the original transplant recipient as well as unoperated and sham-operated dogs. Immunosuppression was maintained with cyclosporine (CyA) and prednisone in the immediate postoperative period and CyA alone thereafter. The DLA-identical dogs demonstrated initial acceptance of the transplant, whereas one of two underwent chronic rejection. Both DLA-disparate dogs had subacute rejection prior to sexual maturity. These results demonstrate that homologous transplantation of prepubertal testes can be an effective method to preserve genotype in DLA-identical dogs. This model may also be useful for studying testis development and immunobiology.

Relative and absolute deficiency of bone marrow endogenous colony stimulating activity in acute myeloid leukemia: relation to response to chemotherapy.

The purpose of this study was to determine possible mechanisms for the recently observed association between insensitivity of acute myeloid leukemia (AML) clonogenic cells to colony stimulating activity (CSA) and poor response to induction chemotherapy. The bone marrow endogenous CSA was determined using semi-solid agar cultures by measuring the response of the AML patients' own clonogenic cells to endogenous CSA. The results show that whereas 31% (5/16) of patients at presentation have deficient bone marrow endogenous CSA production, over 50% (11/21) have relative deficiency of endogenous CSA, due to insensitivity of the patients' clonogenic cells to CSA. Although there is an association between relative deficiency of endogenous CSA and a poor response to therapy, the relationship is not close enough to explain the previously observed highly significant correlation between insensitivity to CSA and poor response to therapy. The CSA-insensitive phenotype and poor response to therapy, one via the tendency to relative endogenous CSA deficiency in the CSA-insensitive group and another via some additional feature of these poor response AML phenotypes which is independent of the presence or absence of endogenous CSA deficiency.

Sensitivity of acute myeloid leukaemia cells to colony stimulating activity: relation to response to chemotherapy.

Agar cultures of acute myeloid leukaemia (AML) cells were used to determine the sensitivity of AML clone forming cells to the specific regulator granulocyte-macrophage colony stimulating activity (CSA). The mean CSA threshold (amount of CSA required to stimulate 0.5 of the clone forming cells) of 27 different AML cell samples varied from normal to an approximately nine-fold increase in CSA requirement. The degree of sensitivity to CSA at presentation was found to be closely correlated to the response to induction chemotherapy in 15 patients. There was a highly significant correlation (P less than 0.001) between the mean CSA threshold and the number of courses of chemotherapy required to induce remission. Also, an increased mean CSA threshold at presentation was associated with a significantly slower decline of marrow blasts following the first course of chemotherapy and a reduced remission rate. Sensitivity to CSA was closely related to the clone size achieved in maximally stimulated cultures of AML cells and this in turn also related to the remission rate and ease with which remission was achieved (presentation marrows, 39 patients). Possible reasons for the linking of these two functional properties of AML cells and their relation to response to chemotherapy will be discussed.