Resumen de Modulation of alloresponses in small and large animals for the improvement of hematopoietic cell transplant outcomes across mhc barriers
Allogeneic hematopoietic cell transplantation (allo-HCT) is a therapy used for the treatment of many lymphohematopoietic neoplasias. Unfortunately, the anti-tumor effects in allo-HCT are often met with graft-versus-host disease (GVHD), a life-threatening side effect. In this thesis, myeloablative and non-myeloablative allo-HCT approaches were used to modulate GVH and host versus graft (HVG) responses to study positive anti-tumor (graft-versus-tumor or GVT) outcomes. We used small and large animal models for our in vivo studies with the aim to control GVHD and maintain GVT effects.
In the mouse, we studied CD100 (an immune semaphorin) and it's effects on immunomodulation of allo-specific responses. In the pig, GVH (in engrafted chimeras) and HVG responses (in animals that rejected their grafts) were investigated.
The studies in mice showed that the effects of CD100 expression on T cells were important in regulating allo-specific responses. CD100-/- T cells were able to maintain graft versus leukemia (GVL) effects while decreased the degree of GVHD in MHC-mismatched myeloablative mouse models. In hematopoietic mixed chimeric swine, donor leukocyte infusions (DLIs) could induce conversion to full donor chimerism without GVHD. The level of chimerism, cell dose and lapsed time post transplant was crucial for successful outcomes, though a significant degree of GVHD was still observed. In animals in which the donor graft was lost, the HVG responses were dominated by potent cellular CD8+ T cells.
Overall, our studies demonstrated that CD100 is a co-stimulatory molecule that can be targeted for the prevention of GVHD without compromising the GVT effects. In swine, the use of DLIs can be safe in mixed hematopoietic chimeras and could be a method to induce GVT effects without compromising GVHD. The parameters of the DLI, donor chimerism and time post transplant need to be further examined before making this protocol extensively used in the clinic.
