Type 1 Diabetes: Goodbye To Transplants?

T1D or Type I Diabetes is a lifelong disease involving disturbance in Insulin hormone that causes high levels of sugar in blood.

Insulin is a hormone produced by special cells called beta cells, in the pancreas. Clusters of  cells called the islets of Langerhans are distributed throughout the pancreas. Islets are made up of several types of cells, including beta cells that produce Insulin.

Body cells require sugar to keep working. Insulin helps to move blood sugar (glucose) into body cells, where the glucose is stored and later used for energy.

In type 1 diabetes, beta cells produce little or no insulin. This causes blood sugar to rise and cells become weak without energy.

An infection or some other trigger causes the body to mistake Beta cells as aliens and kill them as an immune response. That is what we can say at the most, about the cause of T1D. It is called an autoimmune disorder precisely due to this factor.

For late-stage T1D, Islet transplantation is the only curative therapy. Islets are taken from the pancreas of a deceased organ donor, purified, processed, and then transferred into another person. Once implanted, the beta cells in these islets begin to make and release insulin, thus bringing Diabetes under control.

But the transplant therapy has limitations.

First, the benefits do not last long, because the transplanted batch of islets are also attacked and killed by the infection.

Even under chronic immuno-suppression, because of the chronic graft rejection mediated by both auto- and allo-immunity, survival of the transplanted beta cells cannot be guaranteed. The transplants therefore have to be repeated after the efficacy of the earlier one dies out.

Clinical islet transplantation is also restricted by a severe shortage of donor islets. The available donor pancreases are not sufficient to cope up with the demand for T1D.

In USA for instance, organs from about 7,000 deceased donors become available each year. Out of these, less than half are suitable for whole organ pancreas transplantation or for harvesting of islets.

This much is simply not enough. T1D patient population size is overwhelmingly large. In other countries the situation is actually worse.

Can we sustain the cure effected by Islet Transplant and avoid a second transplant? Answer would be yes, if only rejection were eliminated. It's important to do away with rejection.

Rejection is the biggest problem with any transplant, be it of heart, of kidneys, of eyes, of bone marrow, or whatever organ. It's like this:

The immune system is programmed to destroy alien bacteria, viruses, and tissues it recognizes as "foreign," while not attacking "our own" cells.

Due to some goof-up, "our own" beta cells are also seen as "foreign" and are quickly killed. Transplanted islets too are not spared. Immuno-suppressive drugs or anti-rejection drugs like daclizumab (Zenapax), sirolimus (Rapamune), and tacrolimus (Prograf) are needed to keep the transplanted islets functioning, but are not as effective.

Methods are as of now available to reverse auto-immunity, the hostile response of immune system towards "own" cells and other complications associated with Islet Transplants.

Miao Wang and colleagues have studied this aspect on an animal model involving non-obese mice with not late-stage T1D.

They induced mixed chimerism in the animal model and recorded reversal of autoimmunity, elimination of insulitis, and reversal of new-onset of the disease. Not late-stage disease in the non-obese diabetic (NOD) T1D mice only were found to be affected.

Administration of gastrin and epidermal growth factor (EGF) also reverses new-onset but not late-stage T1D in this animal model. Epidermal growth factor (EGF) is a small protein involved in normal cell growth and wound healing. Gastrin regulates gastric acid secretion that helps digestion.

Taken individually the two therapies showed effect on not late-stage mice. The researchers combined the two therapies to develop a line of treatment that succeeded with late-stage T1d mice, as well. Only that these mice had to be non-obese.

The Researchers Team found that combination therapy of induced mixed chimerism under a radiation-free nontoxic anti-CD3/CD8 conditioning regimen and administration of gastrin/EGF works very well with late-stage T1D in NOD mice.

The combination therapy helped regeneration of β cells. The treatment caused birth of new cells and also multiplication of existing cells. Late-stage T1D in non-obese mice was seen to be reversed.

If successfully translated into humans, this combination therapy could replace islet transplantation for T1D patients.


The Paper:

Mixed Chimerism and Growth Factors Augment β Cell Regeneration and Reverse Late-Stage Type 1 Diabetes.

M. Wang, J. J. Racine, X. Song, X. Li, I. Nair, H. Liu, A. Avakian-Mansoorian, H. F. Johnston, C. Liu, C. Shen, M. Atkinson, I. Todorov, F. Kandeel, S. Forman, B. Wilson, D. Zeng,

Source:

Sci. Transl. Med. 4, 133ra59 (2012).
Sci Transl Med 9 May 2012:
Vol. 4, Issue 133, p. 133ra59
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003835