Re: How can the inhibition of dendritic cell maturation in vitro be applied?

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
jdorfman@nih.gov