Posted by Camillo Ricordi on June 05, 1999 at 17:57:48:
In Reply to: Re: anti-cd40L/anti cd154 posted by Sandy Donchess on June 05, 1999 at 00:03:11:
Q:
I know from the DRI web site that islet transplants with donor marrow were/are being done - Jackie Demijohn in Wisconsin was featured. I believe the trial involving islet transplants with donor marrow is a different one than this trial involving CD154. Is this the case?
A:
Yes, it is different and the bone marrow trial is now on hold until this one will be completed because we did not have approval to proceed with two “competing” experimental pilot clinical trials at the same time.
Q:
I've been told that the immune system may have (in my words) different kinds of "attack dog" components, and that some can still fight off infections of the cold/virus type without also attacking the transplanted islets even if infusion of CD154 is done. Is this the case?
A:
Yes, it appears that infections can bypass this “co-stimulatory pathway” required to reject transplanted tissues and organs, and activate directly the immune system in other ways. We still do not know a lot about this antibody’s mechanisms of action, and I would not feel comfortable to include any patient with an active infection.
Q:
The information I've seen indicates that CD154 infusion would be the day before islet transplant, the day of, the day after and periodically for a month or two, then every month for a year or so. It sounds like you would run the risk of not being able to fight off any infection/"non-self" thing present in your body on those days because of this. Is this the case?
A:
See previous answer
Q:
I also have read that none of the monkeys tested have shown any signs of infection. This may sound stupid, but have the transplanted monkeys been surrounded by sneezing, coughing non-transplanted and infused monkeys to see how the transplanted ones do?
A:
The monkeys were in a “normal” monkey environment with other monkeys and not in a “sterile” environment. However, we did not try to have other monkeys sneezing or coughing on them at this time. You have a good point. What we can say so far is that they were exposed to a normal environment and did not get sick.
Q:
A researcher I recently spoke to (if you email me privately - donsa1_AT_dallas.net - I'll give you the details) said that anyone who undergoes an islet transplant at this time will experience failure because of the autoimmune process. This researcher said that anything NOT done with NOD mice or BB rats was essentially to be disregarded. This researcher indicated that the autoimmune process was the problem. I was pretty upset to hear that... Can you tell me your thoughts on what I was told?
A:
I respect this researcher’s point of view. I personally believe there are over 100 ways to cure diabetes in an NOD mouse or in a BB rat, but none of them has worked in humans. I am aware of enough evidence to convince me that this antibody has a powerful effect on autoimmunity. That is why we are going forward with this trial.
Q:
What can you tell me/us about DRI's encapsulation efforts?
A:
We are helping companies to test their products and we are going forward with our own program. I can not discuss other companies’ products, but I can tell you I do not have any miracle to report from our own effort...
Q:
Is there anything going on now that you think will bring about a sufficient supply of islets?
A:
There is a lot going on in islet replication and proliferation. We are currently testing some of these technologies and collaborating with other groups who routinely receive human islets from our program, to continue the research in this direction. It is a very promising field, but extremely challenging.
Q:
Assuming the DRI trial is successful, do you plan on expanding those trials to other parts of the U.S.? If so, when might that be done?
A:
Minneapolis will be strating soon and the NIH center (Harlan) will probably follow. In a second phase there may be also 2 European centers (Milan in Italy and Giessen in Germany), but this will have to be discussed and approved by Biogen. At the present time there is a proposal pending for a network that will include 9 clinical islet transplant center that have agreed to work together to define new strategies for tolerance induction to human islet transplants in patients with type 1 diabetes. These centers will also test any new promising strategy emerging from pilot clinical trials. I was nominated chairperson for this islet group together with Dr. Hering from Minneapolis, and we are very enthusiastic about this possibility.
Q:
Will the DRI do trials on children?
A:
Only after safety will be confirmed in adults.
Q:
What else needs to be done?
A:
1. Verify safety in clinical trials
2. Verify efficacy in clinical trials
3. Test whether the transplanted islet will continue to work long term after discontinuation of the antibody that right now is given at monthly doses for the first year post-transplant
4. Test whether other combination strategies (i.e., anti CD154 + anti CD45RB or anti B7 etc.) or whether the addition of bone marrow/stem cells/bone marrow derived components will allow to induce tolerance with only a short course of inductive immunomodulation
5. Test whether the antibody (or a combination strategy as described above) will be effective in blocking the autoimmune destruction of islets early in the course of the disease or in all cases in which there is still c-peptide (insulin) production and then let the islets regenerate instead of transplanting new ones etc.etc.
6 p.m.: time for my parenting duties.
Best regards,
Camillo Ricordi