Related Documents
Engraftment of Cells from Porcine Islets of Langerhans and Normalization of Glucose Tolerance Following Transplantation of Pig Pancreatic Primordia in Nonimmune-Suppressed Diabetic Rats, The American Journal of Pathology, Published online DOI: 10.2353/ajpath.2010.091193, June 25, 2010
In the thread from my last essay I was asked my opinion of a recent paper from Washington University St. Louis showing progress in islet xenotransplantation. My quick read from the online abstract was positive. This week I decided to get the whole article and comment on it in more detail.
The authors claim “This is the first report of prolonged engraftment and sustained normalization of glucose tolerance following transplantation of porcine islets in nonimmune-suppressed, immunocompetent rodents. The data are consistent with tolerance induction….” This is important because tolerance induction could permit transplantation of islets of Langerhans without immune suppression drugs and without encapsulation — it’s the ideal solution to the immune suppression problem. Did they show true tolerance induction? After studying the paper, I choose the Scottish verdict: “Not proven.”
I have a pretty high standard for tolerance in islet transplantation. Full tolerance allows the islet function expected from the same mass of islets in an autograft. The ideal of islet transplantation is the autograft. In an autograft the islets of a person with pancreatic trauma, so bad that the pancreas must be removed, can be isolated from the pancreas and infused into the diabetic. With as few as 1000 islets per kilogram their diabetes is cured. So what I am saying is that since you truly are tolerant of your own tissue if you are also tolerant of pig islets you would need the same number of islets, or 1000 per kilo for a cure to near normal glucose metabolism.
The number of pig islets to cure these rats was much larger than the number needed for a rat autograft cure. And it does not look like they were cured.
What they did was make rats diabetic with a drug used for that purpose, then implant embryonic cells that are fated to become islets. The embryonic cells cured about 2/3 of the rats. After four weeks the 1/3 with a partial effect were transplanted with either (a) more embryonic islets or (c) mature pig islets. Those with the islets did better than those with more embryonic islets.
The key data are the metabolic results, which is how to judge whether the animals remain diabetic. Below you see Figure 1 with the results of glucose tolerance tests of three groups of rats. The top row are normal nondiabetic rat controls. Each rat is injected with glucose and blood levels of glucose and insulin are measured at 0 (before glucose injection) and 5, 15, 30 & 60 minutes post injection. The top, control, data are typical of all normal animals; glucose rises 200 in five minutes and declines to normal in 30 minutes. As expected insulin levels are highest and 15 and 30 minutes just after the highest glucose.
The second row is the rats treated with pig islets alone, and the third row is the rats treated by embryonic tissue (called E28) then islets four weeks later. In the first five minutes in all the rats there is no time for significant glucose disposal so almost all the injected glucose must remain in the blood; in short, they should all rise the same amount. The controls (which of course have the best glucose disposal so should rise the least) rose 200. The second, islet treated group hardly rose at all and the third group is up only 120, not 200. Where did all the glucose go?
Now look in the lower right graph (F). The shape of the insulin curve is very different from the control rats in the upper right (B). It peaks in 5 minutes, and declines rapidly, even though the glucose levels hardly change! Islets don’t behave that way. Now look at the insulin levels. B & F appear at a glance to have the same levels. But look at the scales. The peak insulin in the control rats (B) is ~0.3 ng/ml. The peak on the treated and cured rats (F) is ~0.05 ng/ml. So the peak insulin levels in the treated rats less than one-fifth of the normal controls.
So to summarize the comparison of the treated rats to the control rats:
Comparison of Glucose Tolerance Test
| Group | Control | Treated |
| Rise in glucose | 200 | 120 |
| Return to euglycemia | 30 min | >60 min |
| Peak insulin, time | 30 min | 5 min |
| Peak insulin, amount | 0.3 ng/ml | 0.05 ng/ml |
The paper claims correctly that fasting euglycemia has been achieved with the treatment. But they also claim “sustained normalization of glucose tolerance.” By the standards of diabetes metabolism these rats are significantly glucose intolerant so this claim is not supported by the evidence.
These workers have made progress in inducing tolerance for pig islets in rats. But from a metabolic point of view the results fall short. I hope that in further studies the glucose tolerance normalizes with a smaller number of pig islets.
Most efforts to induce graft tolerance up to now have relied on some version of anti-CD molecule or OKT3 immunosuppression, both of which can have lasting toxic effects whose ultimate impact on the graft recipient’s health may outweigh any benefits. The important breakthrough in this study is that a non-toxic, more natural, prior transplantation of embryonic cells was used as an alternative route achieve tolerance. This may prove to be a fruitful line of research for all sorts of transplants in the future.
But what is causing the inadequate graft function which you identify? While incomplete tolerance could well account for it, graft injury may also explain some of the effect. When humans receive transplanted organs from cadaver donors, the organs last only about half as long as they do when they come from living donors, even though the ‘cadavers’ from whom the organs are extracted are still ‘alive’ in the sense of being only brain dead but still on life support. How this kind of ‘death’ with a functioning circulation nevertheless damages the health of the grafted tissue remains a mystery, but its effect is well-recognized. Perhaps these islets, no doubt culled from dead animal donors, were showing this same cadaver-source defect. Also, all transplanted organs experience some reduction in function through the trauma of the transplantation process itself, so that an organ which would have continued to operate well for the next 60 years if left in the donor will ordinarily only continue to function for another 20 years after transplantation into a recipient whose immune system does not reject it. The processes involved in this ‘chronic graft pathology’ also remain a mystery. It is possible that all three processes — incomplete tolerance, cadaver-donor-source loss of functional capacity, and transplantation trauma — have all combined to produce the defective islet function in this study.
Scott
Just wanted to tell you thank you for the wonderful program you
put on here at The Fountains. It was very informative, and everyone
learned a great deal. We would love to have an update next time you
are in town. Again, thank you very much.
Kathy
Scott, exellent detailed explaination on this research. Hope someday this dreaded disease
is cured…..that will be THE DAY OF MY LIFE.
Scott, Need your views on the results annouced by sernova on their ” sernova cell pouch “,
do you think this would work on humans ??. To me this result seems intresting.