Islet cell transplantation

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Islet cell transplantation
Langerhanssche Insel.jpg
Microscopic image of an islet of Langerhans (lighter area) surrounded by exocrine pancreas tissue (darker staining).
MeSH D016381

Islet transplantation is the transplantation of isolated islets from a donor pancreas into another person. It is an experimental treatment for type 1 diabetes mellitus. [1] Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the blood.

Contents

Islets are usually infused into the person's liver. [2] If the cells are not from a genetically identical donor the person's body will recognize them as foreign and the immune system will begin to attack them as with any transplant rejection. To prevent this immunosuppressant drugs are used. A study from 2005 showed that islet transplantation has progressed to the point that 58% of the people were insulin independent one year after the operation. [3] A review published 2016 reported a 50 – 70% rate of insulin independence after five years, in five studies from leading transplant centers published 2005 – 2012. [4]

In the period from 1999 to 2004, 471 people with type 1 diabetes received islet transplants at 43 institutions worldwide. [5]

History

The concept of islet transplantation is not new. [6] Investigators as early as the English surgeon Charles Pybus (1882–1975) attempted to graft pancreatic tissue to cure diabetes. Most, however, credit the recent era of islet transplantation research to Paul Lacy's studies dating back more than three decades. In 1967, Lacy's group described a novel collagenase-based method (later modified by Dr. Camillo Ricordi, then working with Dr. Lacy) to isolate islets, paving the way for future in vitro and in vivo islet experiments. [7] Subsequent studies showed that transplanted islets could reverse diabetes in both rodents and non-human primates. [8] [9] In a summary of the 1977 Workshop on Pancreatic Islet Cell Transplantation in Diabetes, Lacy commented on the feasibility of "islet cell transplantation as a therapeutic approach [for] the possible prevention of the complications of diabetes in man". [10] Improvements in isolation techniques and immunosuppressive regimens ushered in the first human islet transplantation clinical trials in the mid-1980s. The first successful trial of human islet allotransplantation resulting in long-term reversal of diabetes was performed at the University of Pittsburgh in 1990. [11] Yet despite continued procedural improvements, only about 10% of islet recipients in the late 1990s achieved euglycemia (normal blood glucose). In 2000, Dr. James Shapiro and colleagues published a report describing seven consecutive people who achieved euglycemia following islet transplantation using a steroid-free protocol and large numbers of donor islets, since referred to as the Edmonton protocol. [12] This protocol has been adapted by islet transplant centers around the world and has greatly increased islet transplant success. [13]

Goals

The goal of islet transplantation is to infuse enough islets to control the blood glucose level removing the need for insulin injections. For an average-size person (70 kg), a typical transplant requires about one million islets, isolated from two donor pancreases. Because good control of blood glucose can slow or prevent the progression of complications associated with diabetes, such as nerve or eye damage, a successful transplant may reduce the risk of these complications. But a transplant recipient will need to take immunosuppressive drugs that stop the immune system from rejecting the transplanted islets.[ citation needed ]

Newer studies have focused their attention towards reducing severe hypoglycemic events, a life-threatening state in type 1 diabetes, rather than focus on removing the need for insulin injections entirely. [14] [15]

Procedure

The process of islet transplantation (illustration by Giovanni Maki). Islet transplantation PLoS Medicine.jpg
The process of islet transplantation (illustration by Giovanni Maki).

Researchers use a mixture of highly purified enzymes (Collagenase) to isolate islets from the pancreas of a deceased donor. Collagenase solution is injected into the pancreatic duct which runs through the head, body and tail of the pancreas. Delivered this way, the enzyme solution causes distension of the pancreas, which is subsequently cut into small chunks and transferred into so-called Ricordi's chamber, where digestion takes place until the islets are liberated and removed from the solution. Isolated islets are then separated from the exocrine tissue and debris in a process called purification.

During the transplant, a radiologist uses ultrasound and radiography to guide placement of a catheter through the upper abdomen and into the portal vein of the liver. The islets are then infused through the catheter into the liver. The person will receive a local anesthetic. If a person cannot tolerate local anesthesia, the surgeon may use general anesthesia and do the transplant through a small incision. Possible risks of the procedure include bleeding or blood clots.

It takes time for the islets to attach to new blood vessels and begin releasing insulin. The doctor will order many tests to check blood glucose levels after the transplant, and insulin may be needed until control is achieved.

Immunosuppression

The Edmonton protocol uses a combination of immunosuppressive drugs, including daclizumab (Zenapax), sirolimus (Rapamune) and tacrolimus (Prograf). Daclizumab is given intravenously right after the transplant and then discontinued. Sirolimus and tacrolimus, the two main drugs that keep the immune system from destroying the transplanted islets, must be taken for life.[ citation needed ]

Limitations

While significant progress has been made in the islet transplantation field, [16] many obstacles remain that currently preclude its widespread application. Two of the most important limitations are the currently inadequate means for preventing islet rejection, and the limited supply of islets for transplantation. Current immunosuppressive regimens are capable of preventing islet failure for months to years, but the agents used in these treatments are expensive and may increase the risk for specific malignancies and opportunistic infections. In addition, and somewhat ironically, the most commonly used agents (like calcineurin inhibitors and rapamycin) are also known to impair normal islet function and/or insulin action. Further, like all medications, the agents have other associated toxicities, with side effects such as oral ulcers, peripheral edema, anemia, weight loss, hypertension, hyperlipidemia, diarrhea and fatigue. [17] Perhaps of greatest concern to the person and physician is the harmful effect of certain widely employed immunosuppressive agents on renal function. For the person with diabetes, renal function is a crucial factor in determining long-term outcome, and calcineurin inhibitors (tacrolimus and ciclosporin) are significantly nephrotoxic. Thus, while some people with a pancreas transplant tolerate the immunosuppressive agents well, and for such people diabetic nephropathy can gradually improve, in other people the net effect (decreased risk due to the improved blood glucose control, increased risk from the immunosuppressive agents) may worsen kidney function. Indeed, Ojo et al. have published an analysis indicating that among people receiving other-than-kidney allografts, 7%–21% end up with kidney failure as a result of the transplant and/or subsequent immunosuppression. [18]

Another limitation to the islet transplantation process is the inflammatory response of the liver. Dr. Melena Bellin is an associate professor of pediatric endocrinology and surgery and director of research for the islet autotransplant program at the University of Minnesota Medical Center and Masonic Children's Hospital. Her research centers on making islet transplants safer and more effective for type one diabetics. The process of infusing islet cells into the liver can trigger an inflammatory response in the body. This reaction leads to a large amount of the newly transplanted islets being destroyed. Losing islet cells decreases the probability of successful insulin production and increases the likelihood of type one diabetes developing again in the patient. Dr. Bellin is currently testing two anti-inflammatory drugs that are already on the market to see if they may be useful in preventing inflammation that destroys islet cells. [19]

Related Research Articles

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the INS gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin, and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins, and fats in food entering the duodenum from the stomach.

Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

<span class="mw-page-title-main">Pancreatic islets</span> Regions of the pancreas

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Pancreas transplantation</span>

A pancreas transplant is an organ transplant that involves implanting a healthy pancreas into a person who usually has diabetes.

<span class="mw-page-title-main">Alpha cell</span>

Alpha cells(α cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Pancreatectomy</span> Surgical removal of the pancreas

In medicine, a pancreatectomy is the surgical removal of all or part of the pancreas. Several types of pancreatectomy exist, including pancreaticoduodenectomy, distal pancreatectomy, segmental pancreatectomy, and total pancreatectomy. In recent years, the TP-IAT has also gained respectable traction within the medical community. These procedures are used in the management of several conditions involving the pancreas, such as benign pancreatic tumors, pancreatic cancer, and pancreatitis.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

Dr. A. M. James Shapiro is a British-Canadian surgeon best known for leading the clinical team that developed the Edmonton Protocol – an islet transplant procedure for the treatment of type 1 diabetes. Dr. Shapiro is Professor of Surgery, Medicine, and Surgical Oncology at the University of Alberta and the Director of the Clinical Islet Transplant Program and the Living Donor Liver Transplant Program with Alberta Health Services.

The Edmonton protocol is a method of implantation of pancreatic islets for the treatment of type 1 diabetes mellitus, specifically "brittle" type 1 diabetics prone to hypoglycemic unawareness. The protocol is named for the islet transplantation group at the University of Alberta in the Canadian city of Edmonton, where the protocol was first devised in the late 1990s, and published in The New England Journal of Medicine in July 2000.

Automated insulin delivery systems are automated systems designed to assist people with insulin-requiring diabetes, by automatically adjusting insulin delivery in response to blood glucose levels. Currently available systems can only deliver a single hormone—insulin. Other systems currently in development aim to improve on current systems by adding one or more additional hormones that can be delivered as needed, providing something closer to the endocrine functionality of the pancreas.

<span class="mw-page-title-main">Blood sugar regulation</span> Hormones regulating blood sugar levels

Blood sugar regulation is the process by which the levels of blood sugar, the common name for glucose dissolved in blood plasma, are maintained by the body within a narrow range. This tight regulation is referred to as glucose homeostasis. Insulin, which lowers blood sugar, and glucagon, which raises it, are the most well known of the hormones involved, but more recent discoveries of other glucoregulatory hormones have expanded the understanding of this process. The gland called pancreas secrete two hormones and they are primarily responsible to regulate glucose levels in blood.

<span class="mw-page-title-main">Insulin oscillation</span>

The insulin concentration in blood increases after meals and gradually returns to basal levels during the next 1–2 hours. However, the basal insulin level is not stable. It oscillates with a regular period of 3-6 min. After a meal the amplitude of these oscillations increases but the periodicity remains constant. The oscillations are believed to be important for insulin sensitivity by preventing downregulation of insulin receptors in target cells. Such downregulation underlies insulin resistance, which is common in type 2 diabetes. It would therefore be advantageous to administer insulin to diabetic patients in a manner mimicking the natural oscillations. The insulin oscillations are generated by pulsatile release of the hormone from the pancreas. Insulin originates from beta cells located in the islets of Langerhans. Since each islet contains up to 2000 beta cells and there are one million islets in the pancreas it is apparent that pulsatile secretion requires sophisticated synchronization both within and among the islets of Langerhans.

<span class="mw-page-title-main">Insulitis</span> Medical condition

Insulitis is an inflammation of the islets of Langerhans, a collection of endocrine tissue located in the pancreas that helps regulate glucose levels, and is classified by specific targeting of immune cell infiltration in the islets of Langerhans. This immune cell infiltration can result in the destruction of insulin-producing beta cells of the islets, which plays a major role in the pathogenesis, the disease development, of type 1 and type 2 diabetes. Insulitis is present in 19% of individuals with type 1 diabetes and 28% of individuals with type 2 diabetes. It is known that genetic and environmental factors contribute to insulitis initiation, however, the exact process that causes it is unknown. Insulitis is often studied using the non-obese diabetic (NOD) mouse model of type 1 diabetes. The chemokine family of proteins may play a key role in promoting leukocytic infiltration into the pancreas prior to pancreatic beta-cell destruction.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

<span class="mw-page-title-main">Brockmann body</span> Endocrine organ in some teleost fish

Brockmann body is an endocrine organ in some teleost fish, and is composed of a collection of islet tissues. The islet tissues are in turn composed of endocrine cells which are the principal sites of insulin synthesis. They are distributed around the spleen and the large intestine. They also secrete other hormones such as glucagon and somatostatin. Hence, Brochmann body is the centre of control of blood glucose level in these fishes. Glucagon is also produced from the intestine, but Brockmann body is the major source. Increased level of glucose stimulate the Brockmann body to release insulin, while inhibiting glucagon. Somatostatin released from Brockmann body inhibits cells to produce insulin and glucagon. In addition it inhibits release of growth hormone from the pituitary. It is named after a German physician Heinrich Brochmann who discovered it in 1848.

<span class="mw-page-title-main">Camillo Ricordi</span> Diabetes researcher

Camillo Ricordi is a diabetes researcher based in Miami, FL. He currently serves as Director of the Diabetes Research Institute, a position he has held since 1996. He is the Chief Academic Officer of the Diabetes Research Institute of the University of Miami and is director of the DRI's Cell Transplant Center. He has been active in stem cell research and its applications to treating diabetes, particularly Type 1 Diabetes. He specializes in pancreatic islet transplantation

References

  1. ↑ Health Quality Ontario (2015). "Pancreas Islet Transplantation for Patients With Type 1 Diabetes Mellitus: A Clinical Evidence Review". Ontario Health Technology Assessment Series. 15 (16): 1–84. ISSN   1915-7398. PMC   4664938 . PMID   26644812.
  2. ↑ Lakey JR, Burridge PW, Shapiro AM (September 2003). "Technical aspects of islet preparation and transplantation". Transplant International. 16 (9): 613–32. doi: 10.1111/j.1432-2277.2003.tb00361.x . PMID   12928769.
  3. ↑ Close NC, Hering BJ, Eggerman TL (March 2005). "Results from the inaugural year of the Collaborative Islet Transplant Registry". Transplantation Proceedings. 37 (2): 1305–8. doi:10.1016/j.transproceed.2004.12.117. PMID   15848704.
  4. ↑ Shapiro, A. M. James; Pokrywczynska, Marta; Ricordi, Camillo (2016-11-11). "Clinical pancreatic islet transplantation". Nature Reviews Endocrinology. 13 (5): 268–277. doi:10.1038/nrendo.2016.178. ISSN   1759-5037. PMID   27834384. S2CID   28784928.
  5. ↑ Shapiro AM, Lakey JR, Paty BW, Senior PA, Bigam DL, Ryan EA (May 2005). "Strategic opportunities in clinical islet transplantation". Transplantation. 79 (10): 1304–7. doi:10.1097/01.TP.0000157300.53976.2A. PMID   15912095.
  6. ↑ Piemonti L, Pileggi A (2013). "25 Years of the Ricordi Automated Method for Islet Isolation" (PDF). CellR4. 1 (1): 8–22. PMC   6267808 . PMID   30505878.
  7. ↑ Lacy PE, Kostianovsky M (January 1967). "Method for the isolation of intact islets of Langerhans from the rat pancreas". Diabetes. 16 (1): 35–9. doi:10.2337/diab.16.1.35. PMID   5333500. S2CID   46277785.
  8. ↑ Kemp CB, Knight MJ, Scharp DW, Lacy PE, Ballinger WF (August 1973). "Transplantation of isolated pancreatic islets into the portal vein of diabetic rats". Nature. 244 (5416): 447. Bibcode:1973Natur.244..447K. doi:10.1038/244447a0. PMID   4200461. S2CID   4273400.
  9. ↑ Scharp DW, Murphy JJ, Newton WT, Ballinger WF, Lacy PE (January 1975). "Transplantation of islets of Langerhans in diabetic rhesus monkeys". Surgery. 77 (1): 100–5. PMID   122797.
  10. ↑ Lacy PE (April 1978). "Workshop on Pancreatic Islet Cell Transplantation in Diabetes sponsored by the National Institute of Arthritis, Metabolism, and Digestive Diseases and held at the National Institutes of Health in Bethesda, Maryland, on November 29 and 30, 1977". Diabetes. 27 (4): 427–9. doi:10.2337/diab.27.4.427. PMID   416985. S2CID   21967127.
  11. ↑ Tzakis AG, Ricordi C, Alejandro R, Zeng Y, Fung JJ, Todo S, Demetris AJ, Mintz DH, Starzl TE (August 1990). "Pancreatic islet transplantation after upper abdominal exenteration and liver replacement". Lancet. 336 (8712): 402–5. doi:10.1016/0140-6736(90)91946-8. PMC   2972674 . PMID   1974944.
  12. ↑ Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (July 2000). "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen". The New England Journal of Medicine. 343 (4): 230–8. doi:10.1056/NEJM200007273430401. PMID   10911004.
  13. ↑ Tekin, Zehra; Garfinkel, Marc R.; Chon, W. James; Schenck, Lindsay; Golab, Karolina; Savari, Omid; Thistlethwaite, J. Richard; Philipson, Louis H.; Majewski, Colleen (October 2016). "Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago". Transplantation Direct. 2 (10): e105. doi:10.1097/TXD.0000000000000609. ISSN   2373-8731. PMC   5068201 . PMID   27795987.
  14. ↑ Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, Kaufman DB, Korsgren O, Larsen CP, Luo X, Markmann JF, Naji A, Oberholzer J, Posselt AM, Rickels MR, Ricordi C, Robien MA, Senior PA, Shapiro AM, Stock PG, Turgeon NA (July 2016). "Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia". Diabetes Care. 39 (7): 1230–40. doi:10.2337/dc15-1988. PMC   5317236 . PMID   27208344.
  15. ↑ Gerber PA, Hochuli M, Benediktsdottir BD, Zuellig RA, Tschopp O, Glenck M, de Rougemont O, Oberkofler C, Spinas GA, Lehmann R (January 2018). "Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation" (PDF). Clinical Transplantation. 32 (1): e13153. doi:10.1111/ctr.13153. PMID   29140547. S2CID   22996728.
  16. ↑ Robertson RP (February 2004). "Islet transplantation as a treatment for diabetes - a work in progress". The New England Journal of Medicine. 350 (7): 694–705. doi:10.1056/NEJMra032425. PMID   14960745. S2CID   1307522.
  17. ↑ Hirshberg B, Rother KI, Digon BJ, Lee J, Gaglia JL, Hines K, Read EJ, Chang R, Wood BJ, Harlan DM (December 2003). "Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience". Diabetes Care. 26 (12): 3288–95. doi: 10.2337/diacare.26.12.3288 . PMID   14633816. Full text
  18. ↑ Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, Arndorfer J, Christensen L, Merion RM (September 2003). "Chronic renal failure after transplantation of a nonrenal organ". The New England Journal of Medicine. 349 (10): 931–40. doi: 10.1056/NEJMoa021744 . PMID   12954741. S2CID   12270800.
  19. ↑ Brody, Barbara. "Making Islet Cell Transplants Safer". Diabetes Forecast.
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