|MadSci Network: Immunology|
Hello Clara, I'll start with your specific questions: 1. Would they be used as systemic antirejection therapy? In principle, yes. I don't see any other way that they could work unless they were able to affect all of the patient's T cells, as any unaffected T cells capable of rejecting would eventually circulate to the transplant site and start a reaction. 2. would the body's ability to fight invading pathogens be limited? Again, in principle, no. The tolerizing dendritic cells should affect only T cells that recognize them and should leave other T cells alone. Current methods of preventing rejection use drugs such as cyclosporin and FK506 that are much more generally immunosuppressive because they affect most or all T cells to a greater or lesser extent. This specificity (as well as much lower toxicity!) that could be expected out of dendritic cell based tolerization (if it could be made to work) is one of the major attractions of such an approach. This is why some scientists are actively researching such techniques even though immunosuppressive drugs work reasonably well to prevent rejection. More information. So far, using dendritic cells to promote tolerance is in a very early, experimental stage. All of the experiments we can find use mice and rats and we know of no successful attempts (or even unsuccessful ones) using humans. The problem is that dendritic cells in some states are used by the body to make immune responses more powerful rather than less powerful. So, tweaking them properly and in a way that is both complete and long lasting to promote tolerance is difficult to do. There is some evidence that dendritic cells do this in the body normally in some cases. Again, a mouse experiment. There are mice that were engineered to express a flu protein in their parenchymal tissues, which include the heart, lung, salivary glands and part of the male reproductive organs. Flu-specific T cells were transferred to these mice and became tolerant, and this tolerance was dependent upon the particular flu antigen being presented by a bone marrow derived cell type (mostly white and red blood cells) that is thought to be dendritic cells. (described in a review Fairchild PJ and Waldmann H, Dendritic cells and prospects for transplantation tolerance, Current Opinion in Immunology 200, 12:528-535) We also found a paper where researchers working in rats were able to manipulate dendritic cells to affect graft rejection. Treatment with two day cultured dendritic cells prolonged graft survival while treatment with ten day cultured dendritic cells actually promoted faster rejection than no treatment. According tot his sdea, the two day cultured cells were more tolerogenic while the longer cultures contained stimulatory cells. There are a few points to keep in mind about this study, whcih are general reasons why this therapy, at least as far as I can see is pretty far from use in the clinic. 1) The dendritic cells were not pure and other cell types in the population amy play a role. 2) This may not work as consistently in people, which are genetically diverse, much more than the experiemntal rats. 3) All the heart grafts were eventually rejected, even with tolerogenic DC treatment. 4) The authors suggest a difference between the two day and ten day cultured cells in their phenotype; but, I have trouble imagining that this is the only difference and I'm inclined to doubt it is the *reason* they are tolerogenic. We'd want to know how to tell tolerogenic dendritic cells apart rather well to be sure that we were injecting only tolerogenic cells into people for treatment! I hope this helps. If you have any questions or if have read the review I quoted above or any other papers (I didn't have time to finish it myself) and have questions, you can email me back and I'll try to help. If you have trouble getting a copy, you can email me the address of your school and I'll mail a copy. Jeff Dorfman and Sabine Stoll firstname.lastname@example.org
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