Mathematical modeling of cellular differentiation upon hematopoietic stem cell transplantation.

摘要

Allogeneic hematopoietic cell transplantation (HCT) following chemo- and/or radiotherapeutic conditioning is a standard treatment for certain malignant and nonmalignant hematological disorders. The allotransplant generates anti-recipient effects, including beneficial graft-versus-leukemia responses and undesirable graft-versus-host reactions. Conventional HCT uses high doses of conditioning therapy that ablates the recipient's marrow and causes secondary injury. Non-myeloablative transplantation incorporates low intensity conditioning that mitigates mucosal injury and permits the transplanted cells to engraft without prior marrow ablation. To better understand this process and to aid transplant hematologists in optimizing HCT strategies, we developed a mathematical model of the hematopoietic cell reconstitution therapy in humans. The ordinary differential equation model reflects the proliferation, differentiation, and interactions of the host and donor leukocyte lineages with cancer cells. The model is adapted from the Marciniak-Czochra unilineage hematopoietic stem cell model and extended to address: 1. multilineage differentiation into four mature leukocyte cell types (neutrophils, lymphocytes, monocytes, and eosinophils) 2. activation, differentiation, proliferation, and maturation process of these cells 3. chimerism and 4. myeloablative and non-myeloablative conditioning. Unknown model parameters were tuned so the simulated peripheral leukocyte dynamics fit available averaged human subject data. In an IRB approved study, de-identified cell counts from 7 days prior to donor cell infusion to 30 days post transplantation were used. The mathematical model presented integrates current knowledge of the physiology with clinical observations to better understand the influences of chemotherapy, immunosuppression, and radiation therapy on the evolution of the peripheral leukocyte blood cell counts following conventional and non-myeloablative conditioning. Future work will optimize the therapeutic strategies to promote graft-versus-leukemia while mitigating graft-versus-host disease.