Enhancing dendritic cell immunotherapy for melanoma using a simple mathematical model.

BACKGROUND: The immunotherapy using dendritic cells (DCs) against different varieties of cancer is an approach that has been previously explored which induces a specific immune response. This work presents a mathematical model of DCs immunotherapy for melanoma in mice based on work by Experimental Immunotherapy Laboratory of the Medicine Faculty in the Universidad Autonoma de Mexico (UNAM). METHOD: The model is a five delay differential equation (DDEs) which represents a simplified view of the immunotherapy mechanisms. The mathematical model takes into account the interactions between tumor cells, dendritic cells, naive cytotoxic T lymphocytes cells (inactivated cytotoxic cells), effector cells (cytotoxic T activated cytotoxic cells) and transforming growth factor ß cytokine (T G F-ß). The model is validated comparing the computer simulation results with biological trial results of the immunotherapy developed by the research group of UNAM. RESULTS: The results of the growth of tumor cells obtained by the control immunotherapy simulation show a similar amount of tumor cell population than the biological data of the control immunotherapy. Moreover, comparing the increase of tumor cells obtained from the immunotherapy simulation and the biological data of the immunotherapy applied by the UNAM researchers obtained errors of approximately 10 %. This allowed us to use the model as a framework to test hypothetical treatments. The numerical simulations suggest that by using more doses of DCs and changing the infusion time, the tumor growth decays compared with the current immunotherapy. In addition, a local sensitivity analysis is performed; the results show that the delay in time " τ", the maximal growth rate of tumor "r" and the maximal efficiency of tumor cytotoxic cells rate "aT" are the most sensitive model parameters. CONCLUSION: By using this mathematical model it is possible to simulate the growth of the tumor cells with or without immunotherapy using the infusion protocol of the UNAM researchers, to obtain a good approximation of the biological trials data. It is worth mentioning that by manipulating the different parameters of the model the effectiveness of the immunotherapy may increase. This last suggests that different protocols could be implemented by the Immunotherapy Laboratory of UNAM in order to improve their results.

ATPase and MHC class II molecules co-expression in Rana pipiens dendritic cells.

Mammalian Langerhans cells are antigen-presenting cells located in different epithelia. These cells have a characteristic ultrastructural pattern, present a plasmatic membrane ATPase activity and constitutively express class II molecules of the major histocompatibility complex. ATPase-positive dendritic cells that are morphologically similar to Langerhans cells have also been found in amphibian epidermis. In order to demonstrate that ATPase-positive dendritic cells of amphibian epidermis express class II molecules and are present in other stratified epithelia, histochemical and immunohistochemical as well as ultrastructural analysis were performed. ATPase-positive dendritic cells and class II-positive dendritic cells were observed in epidermis, nictitant membrane and cornea. In epidermis the number of ATPase-positive dendritic cells was 656+/-186/mm2 while class II-positive dendritic cells was 119+/-45/mm2. Some ATPase-positive dendritic cells showed co-expression of class II molecules. These results suggest the existence of dendritic cell subsets in amphibians as is clearly demonstrated in mammals.

CD11c decrease in mouse thymic dendritic cells after vanadium inhalation.

Vanadium (V) is a transition metal found in air adsorbed onto suspended particles. As a result, urban populations are often exposed to this element as a constituent of particulate matter (PM). One aspect of the myriad toxicities that might arise from these exposures is altered immune responses. Previous reports from the laboratory reported modifications in splenic architecture - with germinal center hyperplasia and a suppressed humoral immune response - in mice that had been exposed to vanadium agents via inhalation. This paper reports a decrease in the presence of the CD11c surface marker on mouse thymic dendritic cells (DC) as a result of host exposure to vanadium (here, in the form of vanadium pentoxide; V(2)O(5)) over a period of 4 weeks. All results were obtained using immunohistochemistry and flow cytometry. It is surmised that this decrease might induce a dysfunction, including possible negative selection of T-cells, which could increase the presence of autoreactive clones in the exposed host. Such an outcome could, in turn, increase the risk for development of autoimmune reactions in different organs specifically, and of autoimmune diseases in general in these V-exposed hosts.

Non-specific esterase-positive dendritic cells in epithelia of the frog Rana pipiens.

Langerhans cells are antigen-presenting cells located in epithelia and have a dendritic outline, a convoluted nucleus surrounded by an electron lucent cytoplasm with sparse organelles and occasionally containing the characteristic Birbeck granule; their membrane contains class II molecules of the major histocompatibility complex and a strong membrane reactivity for both ATPase and non-specific esterase. Despite increasing knowledge about mammalian Langerhans cells, only a few studies have examined the possible occurrence of Langerhans-like cells in lower vertebrates. Our group has previously demonstrated the presence of dendritic cells in different epithelial membranes co-expressing a strong membrane ATPase reactivity and class II molecules of the major histocompatibility complex in the frog Rana pipiens. Adding another criterion in the characterization of Langerhans-like cells in amphibians, we now report evidence for the expression of membrane non-specific esterase reactivity in dendritic cells located in the epidermis, nictitant membrane and cornea with topographical and light and electron microscopical characteristics identical to those previously described for dendritic cells positive for ATPase and major histocompatibility complex class II in Rana pipiens. We postulate that, taking all this data together, these dendritic intraepithelial cells constitute the amphibian counterpart of mammalian Langerhans cells.