Answers for a Cure-A Q&A with Camillo Ricordi, MD
Prompted by Scott King's April 1998 column ("Questions for a Cure"), Camillo Ricordi, MD, sent in his response to Scott's series of questions regarding islet cell transplantation. Ricordi is a Professor of Surgery and Medicine and Chief of the Division of Cellular Transplantation, Department of Surgery at the University of Miami School of Medicine and the scientific director of the Diabetes Research Institute in Miami. He is a pioneer in the field of islet cell transplantation and is credited with developing an islet cell isolation technique that allows researchers and doctors to obtain enough islets from a single pancreas to treat a recipient.
Scott King: Is a trial without immunosuppression a realistic possibility? If so when?
Camillo Ricordi, MD: Yes. As a matter of fact, there is at least one that has received FDA approval to begin, and I am sure you will hear more about similar trials in the near future. I predict, however, that more trials will still include some form of immunosuppression.
There will be a growing trend towards the use of agents that modulate the immune system rather than suppress it because of the well-known side effects of the chronic use of immunosuppressive drugs. I still believe that some sort of short-term modulation of the immune system immediately after an islet transplant will be necessary.
As yet, we still do not know how long after transplantation it may be possible to discontinue immunosuppressive drugs. Most importantly, we do not know in which patients (and when) complete discontinuation of immunosuppression will be feasible.
King: Is immunosuppression justified in diabetics not otherwise receiving such drugs for a kidney transplant?
Ricordi: Risk/benefit ratios have to be carefully considered in each pilot trial. Immunosuppression may be indicated in patients with severely impairing diabetes, with hypoglycemia unawareness, or in patients unable to reduce HbA1c levels despite intensive insulin treatment.
King: Which method do you favor to isolate the transplant from the immune system?
Ricordi: I personally do not favor any currently available method of isolating transplanted islets over another. I believe that there are still some problems that may affect long-term survival of transplanted islets into devices, or using encapsulation technologies in large mammals, including humans. However, substantial progress has been made in this field. I do not exclude that a couple of such approaches will see clinical testing before the end of 1998.
King: Was your trial done on a dog (or other higher mammal) or just rodents?
Ricordi: This relates to the question before. All pilot clinical testing that we will be performing utilizing devices or encapsulation technologies will have to have shown safety and efficacy in higher mammals before being considered for clinical application.
King: What drugs were used at the time of the transplant? What was used as the trial continued?
Ricordi: In clinical trials involving encapsulation technology, immunosuppressive drugs have been used in some patients and this has generated some confusion. On one hand it is believed that immunoisolation technology will not require immunosuppression, yet on the other, some of these trials use immunosuppressive treatment. The use of immunosuppression may be dictated by regulatory issues that require that phase 1 trials be conducted in individuals already receiving immunosuppression (i.e. organ transplant recipients).
However, I don't exclude that some form of modulation of the immune system, if not immunosuppression, may be indicated in all immunoprotected grafts. For example, anti-inflammatory therapy or antioxidant therapy may be indicated in the early post-transplant period. These treatments could be most likely discontinued after a few weeks.
King: How many islets (islets/kg of body weight) were needed?
Ricordi: The optimal number of islets per kilogram needed is also yet to be determined. From the data of the International Transplant Registry, it seems that the best clinical results are obtained in islet transplants that have been performed with more than, or at least, 6,000 islets per kilogram of a recipient's body weight. However, we know that insulin independence can be achieved with fewer islets per kilogram.
Many factors play a substantial role in this, including islet viability, the number of islets that are lost in the immediate post-transplant time, and if you use devices or encapsulation - the relative degree of inefficiency of the bioartifical system. For example, you may need to "load" many more islets to obtain a metabolic response that is comparable to that which can be obtained by free islet transplant. In addition to encapsulation, the islet transplant site may substantially affect the number of islets required for transplantation.
King: Was the implant repeated?
Ricordi: This, as well as many of the questions that follow, are probably in reference to trials of encapsulated islets. Presently, we do not repeat islet transplants with non-encapsulated islets because one of the endpoints of this procedure is to evaluate how long an islet transplant can function in a site of implantation that is not the native pancreas.
When we were first able to separate and purify large numbers of human islets, making it possible to transplant patients with type 1 diabetes, the first questions the scientific community asked were: Would these islets be able to reverse diabetes? Would they exhaust or fail naturally within a year or two because the transplanted islets are not in their natural location and because of the lack of growth inducing factors at the transplant site?
This has not been the case in the few islet transplants that have not been rejected, and we now have patients with functioning islet grafts for over seven years. We know that islet allografts within the liver have maintained complete insulin independence for approximately five years. There is evidence, therefore, indicating that islets can indeed achieve long-term function, normalizing HbA1c levels and leading to a degree of metabolic control comparable to that of intensive insulin treatment but without the risks associated with severe hypoglycemia. The challenge now is to produce these results in all patients and without the requirement for long-term immunosuppression.
King: Was the transplant recipient given a glucose tolerance test? If so, how normal was the response?
Ricordi: The results of glucose tolerance tests or similar provocative tests (i.e. Sustacal) performed in the few patients with long-term islet function have shown an initial decrease in function of the transplanted islets, with subsequent stabilization of the response at levels that are inferior compared to a normal control, but which allowed to maintain HbA1c in the normal range in the absence of severe hypoglycemia (Diabetes 46:1983-89, 1997).
This decreased response could be due in part to the immunosuppressive drugs used, which are known to be diabetogenic (cause diabetes) and impose a 2.5 fold increase in the metabolic demand to transplanted islets. We now have encouraging results in pre-clinical trials indicating that in the absence of "diabetogenic" agents islet transplants can produce normal responses following glucose tolerance tests.
King: Does the implant cause fibrosis (i.e. a foreign body reaction) that would starve the transplant of nutrients?
Ricordi: This also relates to encapsulation and devices. Only recently have scientists determined that it's not just the biocompatibility of the material used that can induce the foreign body reaction resulting in fibrosis around the implant, but it is also the quality and the characteristics of the tissue within the device or capsule that can result in shed microscopic tissue fragments. These fragments can diffuse outside the device or protective membrane and still evoke an inflammatory or immune response that can significantly affect the reaction around the implanted cells.
King: Are all the islets functional in the recovered implant?
Ricordi: This is a very important question. It is critical that islet recovery be demonstrated at the pre-clinical level. It is equally important to demonstrate morphologic and functional integrity of the encapsulated islets at the end of the study, to exclude that the metabolic effect observed was related to partial function or islet regeneration in the native pancreas.
King: If your work relies on xenotransplants (transplants from another species), is there any risk of infection?
Ricordi: This is another important question, and even though we are continuing some research on xenotransplantation, we are aware of the risks of infection. Right now, we are concentrating on pilot clinical trials of islet transplantation (human-to-human).
King: Will the FDA allow a person not receiving immune system suppression to get an islet transplant?
Ricordi: Yes. The FDA has already granted permission for this kind of trial.
King: Fewer than 5,000 cadavers provide organs of any kind every year, and only 1,000 pancreases are recovered each year. Is this enough to make your work a viable option?
Ricordi: This scenario indicates that we must improve pancreas procurement. These are enough pancreases to determine whether any procedure will work. Some of the funds available for diabetes research should be allocated to define strategies enabling the transplant of two or more recipients from any single donor (as we are already doing in pre-clinical trials). Then the problem would be to create public and scientific awareness/education so that most of the pancreases aren't lost simply because they are not procured. This is such an important issue that it may deserve a separate editorial.
It is also important to note that some of the best human pancreases available for islet isolation are from patients whose organs are routinely turned down for organ transplant purposes. So it is quite possible that islet cell transplantation will not interfere with the allocation of organs for pancreas transplant.Click Here To View Or Post Comments