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Under the Microscope

Under the Microscope with Alberto Pugliese, M.D.

The immune system serves as our built-in “radar,” continuously scanning the body to determine what is “self” and what is “foreign” and needs to be eliminated. This process of checks and balances is not perfect, and despite many mechanisms of control and regulation, the immune system can make mistakes. Such mistakes can result in autoimmune diseases in which, like “friendly fire,” our immune system accidentally destroys its own tissues or cells.

To better understand autoimmunity, the process that causes type 1 diabetes, picture a seesaw that you’d find in a playground. On one end is a group of immune system cells, called effector cells, that are responsible for targeting and destroying what is seen as “foreign.” On the other end are regulatory T cells, or T-regs, which control the effector cells and prevent them from attacking the body’s own cells, or “self.” When the two sides are balanced, the immune system works properly.

When there are not enough T-regs, however, a dangerous imbalance occurs. The effector cells, having more “weight,” can take control and mistakenly destroy “self” cells, like the insulin-producing beta cells in the pancreas. 

Restoring this balance is key to reversing autoimmunity and it’s the focus of Dr. Alberto Pugliese, head of the DRI’s Immunogenetics Program. For the past several years, he and the DRI’s Dr. Thomas Malek have been studying the role of IL-2 (interleukin 2), a natural substance released by certain types of immune cells.  IL-2 plays a critical role in the function of both effector cells and T-regs. High dose IL-2 has been used in cancer patients as a way to stimulate the effector cells to eliminate the cancer. Dr. Malek’s landmark studies in experimental mice showed that IL-2 also plays a key role in maintaining proper T-reg function, thus preventing autoimmunity.

This past year, Drs. Pugliese and Malek showed that human T-regs are highly sensitive to IL-2 and respond to much lower doses compared to effector and memory immune cells, which need much higher levels of IL-2 to initiate a response.  Other researchers also showed that low-dose IL-2 improved T-reg function and was able to reverse autoimmune diabetes in experimental models. These important findings point to the use of IL-2 itself, at low dose, as a potential therapy for the control of autoimmunity by restoring this critical immunological balance.

Low-dose IL-2 may also play an important role in re-activating a large percentage of beta cells that Dr. Pugliese believes haven’t been destroyed at all, but are just non-functioning. He further explains this area of research in the following interview.

Q. What is the difference between “effector cells” and T-reg cells?

A. Effector cells are immune cells that mediate the immune response, often killing or promoting the killing of targeted cells. T-reg cells regulate the function of the immune system and can inhibit the effector cells. They are critical to regulate the immune system and to prevent excessive or unwanted immune responses, such as the ones that can cause an autoimmune disease like type 1 diabetes.

Q. What is IL-2 and how has it been used for other diseases?

A. IL-2 is a natural substance that supports the function of the immune system, promoting the development, survival and function of immune cells, in particular of those called lymphocytes. These include both the effector cells and the Treg cells.

IL-2 has been primarily used in clinical trials in conditions such as cancer and AIDS to boost the immune response against cancer cells or the HIV virus. In that setting it is given at high doses but unfortunately efficacy has been limited. 

Q. How will low doses of IL-2 help to rebalance the immune system? 

A. We are learning that T-reg cells are very sensitive to IL-2, and can respond to it very effectively even at very low doses. At those low doses, stimulation of effector cells would be minimal, if any. Thus, low dose IL-2 could rebalance the immune system towards a more regulated state, with increased Treg function and better control of unwanted responses. 

Q. Low dose IL-2 has recently been used in clinical trials for type 1 diabetes. What were the results of those studies?

A. Results from the first low dose IL-2 trial conducted in France by Dr. David Klatzmann and his team have been recently reported. Three different low doses of IL-2 have been given for a short period of time to patients with type 1 diabetes, to assess safety and whether IL-2 increased T-reg cells. Overall, there was no evidence of diabetes worsening and at these doses IL-2 was safe with rare side effects, which were never serious. There was also evidence the Treg cells increased in several patients. In some, there was evidence that the effector immune responses associated with type 1 diabetes were being inhibited. These results are very promising and we are directly collaborating with Dr. Klatzmann on the study of patients in the trials. For example, together with Dr. Tom Malek, a leading IL-2 expert that co-leads this DRI project, we will examine samples from patients from this first trial to understand better the cellular and molecular changes induced by the treatment, also in relation to how well a patient responded to the therapy. This will also help identify which patients are more likely to benefit from low dose IL-2 therapy.    

Q. How does this research fit into our BioHub approach?

A. The BioHub includes local delivery of medications that can support the function of insulin-producing cells and control the immune system. Low dose IL-2 could be given in this context and, by promoting immune regulation, improve the function, survival of insulin-producing cells in the BioHub. It would also help reduce side effects if it could replace immunosuppressive drugs or reduce their dosage. Based on current knowledge, IL-2 might be effective without using immunosuppressive drugs, but this remains to be tested.

Q. In a recent Insulin Nation interview, you commented that beta cells are not being entirely destroyed, but rather “switched off.” Can you further explain why you believe this to be the case and why this therapy might be the key?

A. I think that evidence is building up that supports this contention. We have been studying transplant recipients who, after years of normal transplant function, developed diabetes once again because the autoimmune process has been reactivated and now attacks the transplanted pancreas, but there is no rejection [of note, since these patients are treated with immunosuppressive drugs to prevent rejection. This suggests that anti-rejection drugs do not always prevent or control autoimmunity.]

When we examine the transplanted pancreas, we find that only about 30 percent of the pancreatic islets, the structures that contain the insulin-producing cells, appear affected. Thus, a large proportion of insulin producing cells are still there and apparently intact. However, even after specific metabolic tests that stimulate insulin secretion, we observe no or minimal secretory response from these patients. In other words, there are plenty of insulin-producing cells, but they are not functioning.

Moreover, as co-director of the JDRF nPOD (Network for the Pancreatic Organ Donors with Diabetes, JDRFnPOD.org), I am involved in ongoing studies of the pancreas from organ donors with type 1 diabetes. In many of those donors, we are observing the presence of significant numbers of insulin producing cells even many years after disease diagnosis.

Lastly, recent studies have reported that insulin secretion persists in many patients for years after diagnosis. All of the above and other studies not mentioned here point to the chronic nature of the disease process, the potential ability of insulin-producing cells to survive and/or regenerate, both of which suggest a wider therapeutic window for patients with type 1 diabetes.

Typically, most trials have been conducted within 3 months of diagnosis, but based on the above, I suspect that patients may be treated and perhaps recover, at least partially, even years after diagnosis. At the same time, a dysfunctional state may exist, especially at the time of diagnosis that may contribute significantly to the diabetes symptoms besides the actual loss of insulin-producing cells.

Thus, improved regulation of the immune system and therapies that improve the function of insulin-producing cells may be synergistic and afford benefit to patients with type 1 diabetes, hopefully even at later disease stages than previously thought. 




 

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