Intrahepatically Transplanted Islets—Strangers in a Strange Land

R. Paul Robertson

Pacific Northwest Research Institute and the University of Washington Seattle, Washington

Address all correspondence and requests for reprints to: R. Paul Robertson, M.D., Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, Washington 98122.

In his book Stranger in a Strange Land, Robert A. Heinlien imagined what would happen if the offspring born of human parents living on Mars were suddenly translocated to Earth. At the beginning of the saga, earthling behavior confuses, confounds, and delights the naïve Martian. However, as the plot unfolds, the Martian, alternatively verging on discorporation and grokking his new environment, profoundly influences the earthlings he encounters. The theme is one of a stranger who is challenged by a radically new environment, yet over time profoundly alters the lives of those around him. In some respects, intrahepatic islet transplantation is an analogous situation. What unanticipated consequences might be set in motion when clusters of cells called islets are transplanted from a pancreas of a dead human donor into the liver of a diabetic recipient?

Talk about an out-of-body experience! Normally, the islet is comfortably tucked away deep in the abdomen within the pancreas, safely adrift in a sea of exocrine tissue. All around it are acinar cells busily churning out digestive enzymes they will deliver into the pancreatic duct and then the intestine, but the islet remains safe because of its specialized vascular supply and protective membrane wrap. It happily goes on from one day to the next, alternatively supplying its human host with insulin and glucagon, ever responsive to the level of glycemia presented to it. Suddenly, one day a threatening shadow appears and a destructive force overtakes the host. Death ensues, and an organ donor is born.

In this scenario, the patient had elected to donate after death his or her organs to sustain the life of another human being. The brain dead patient is kept on life support measures for hours until the organs can be removed. Among them is the pancreas, and within the pancreas are the islets, wondering what in the world is happening. Soon they find themselves in an islet isolation laboratory, complete with gowned scientists and whirring refrigerated centrifuges. Carefully, the pancreas is stripped of extraneous connective tissue and then dissected so that the pancreatic duct is accessible to collagenase injection. Cruel irony! The islet that had been protected all its life from digestive enzymes is now deliberately exposed to an enzyme whose job it is to dissolve the normal architecture of the pancreas that protected it from exocrine enzymes. Soon, the islet finds itself awash in cold buffers and biochemical gradients, all the time being centrifuged at dizzying speeds so that it can be totally isolated from the exocrine cells that embedded it all its life. During this process, the islet sees many of its companions dying in the process. Somehow, it lives. Then it is packaged with the other surviving islets, brought to a radiology suite, and sent tumbling down an iv line into a catheter lodged in the portal vein of a diabetic patient who has been plagued with metabolic instability despite intensive insulin-based therapy. The swift current of the portal vein carries it into narrower and narrower passages until it can go no further. Abruptly, it is lodged deep within a strange land—the liver. This is an organ that the islet used to control by dint of its insulin and glucagon secretion. Now the islet is within the liver’s control, and no longer are there familiar exocrine cells surrounding it. Instead, there are strange cells called hepatocytes that make glycogen and glucose and other threatening creatures called resident macrophages that march threateningly toward the newcomer. And there is very little oxygen! The blood that bathes it contains drugs that are toxic! What in the liver is going on?

What is going on is a process known as intrahepatic allotransplantation of isolated pancreatic islets in a metabolically unstable type 1 diabetic patient who has been given immunosuppressive drugs. This is a procedure that was first successful in rodents in 1972 (1) when it was predicted to be soon the definitive treatment for insulin-dependent diabetic patients. Over a quarter century of frustration followed as failure after failure was encountered when this procedure was attempted in humans. Significantly, the procedure was successful in the early1980s using the autotransplantation paradigm (2). Patients who were not diabetic but who had chronic, painful pancreatitis could undergo pancreatectomy for pain relief and then receive an intraportal infusion of their own islets without the need for immunosuppressive drugs. This procedure has prevented the onset of diabetes in pancreatectomized patients for up to two decades (3). Consistent success in allotransplanted diabetic patients was elusive, however, until the innovative Edmonton protocol was introduced in 2000 (4). Now, by using an immunosuppressive drug regimen that avoids glucocorticoids and includes anticytokine drugs, diabetic patients are experiencing up to 80% success rates in the initial years of alloislet transplantation (5). Not all patients have perfectly normal glycemia, but they do have normal levels of hemoglobin A1c and do not have the episodes of hypoglycemia and poor symptom awareness. This is no mean feat.

When one considers the plight of the islet wrenched from its familiar surroundings and put into the strange environment of the liver where it needs to find new blood supply and oxygenation, it is not surprising that two pancreases, on average, are now required to render recipients insulin free with normal hemoglobin A1c levels (4). Added to this problem are the inherent ß-cell-toxic properties of calcineurin inhibitors that are used for immunosupression (6). Researchers in this area are taking on the challenge to dramatically decrease the islet loss that is encountered during the isolation process, as well discovery of less toxic drugs for immunosupression or, better yet, methods to induce tolerance so that immunosupression can be avoided altogether. In the meantime, one can only be amazed at the ability of islets to survive intrahepatic transplantation.

As beautifully illustrated by two articles in this issue of JCEM, a major issue for islet survival is the establishment of new vascular connections. Carlsson et al. (7) document just how tenuous the islet’s existence is because of the markedly decreased vascular density and p02 in its environment. This points out the need to discover methods of inducing better vascularization in islet transplantation sites before transplantation. Hirschberg et al. (8) provide the important observation in primates that islet capillary formation appears not to be present 5 d after intrahepatic transplantation, but is present by 30 d. We are left wondering when between 5 and 30 d effective capillary formation is established and how the hypoxic islet survives at all until this occurs. The authors point out that a thin endothelial layer eventually separates the islet from the portal vein lumen and suggest this should allay concerns about high concentrations of toxic immunosuppressive drugs in the portal blood. However reassuring, the islet still has to cope with portal blood drug levels in the early days after transplantation, and it is not known whether or not drugs diffuse across the newly formed epithelial layer. Both of these articles illustrate the need for more intensive research designed to characterize and improve the environment into which islets are now being transplanted. A related concern is the inability of intrahepatic islets to release glucagon during hypoglycemia. Intrahepatic islets have been shown to release glucagon during stimulation with arginine (9), but strangely do not release this hormone when recipients’ blood glucose is lowered to levels as low as 40 mg/dl (10, 11). This appears to be peculiar to the intrahepatic site, because islets placed in the peritoneal cavity (12) release glucagon normally during hypoglycemia.

Now that successful alloislet transplantation for diabetic patients has become a reality, the challenge is to improve current methods of islet isolation and to create a friendlier environment for the transplanted islet. The former may involve better islet protection during procural, less rigorous purification, and periods of in vitro culturing before transplanting. The latter may involve discovery of methods to accelerate vascularization of the graft and perhaps the use of nonhepatic sites. Achievement of these goals are feasible so that it should be only a matter of time before the transplanted islet groks its strange journey as more friendly than threatening.

Acknowledgments

Footnotes

This work was supported by NIH Grant NIDDK RO1-39994.

Received October 17, 2002.

Accepted October 17, 2002.

References

  1. Ballinger WF, Lacy PE 1972 Transplantation of intact pancreatic islets in rats. Surgery 72:175–186[Medline]
  2. Najarian JS, Sutherland DE, Baumgartner D, Burke B, Rynasiewicz JJ, Matas AJ, Goetz FC 1980 Total or near total pancreatectomy and islet autotransplantation for treatment of chronic pancreatitis. Ann Surg 192:526–542[Medline]
  3. Robertson RP, Lanz KJ, Sutherland DE, Kendall DM 2001 Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 50:47–50[Abstract/Free Full Text]
  4. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV 2000 Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen [see comments]. N Engl J Med 343:230–238[Abstract/Free Full Text]
  5. Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM 2002 Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148–2157[Abstract/Free Full Text]
  6. Paty BW, Harmon JS, Marsh CL, Robertson RP 2002 Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation 73:353–357[Medline]
  7. Carlsson P-O, Palm F, Mattsson G 2002 Low revascularization of experimentally transplanted human pancreatic islets. J Clin Endocrinol Metab 87:5418–5423[Abstract/Free Full Text]
  8. Hirshberg B, Mog S, Patterson N, Leconte J, Harlan DM 2002 Histopathological study of intrahepatic islets transplanted in the nonhuman primate model using Edmonton protocol immunosuppression. J Clin Endocrinol Metab 87:5424–5429[Abstract/Free Full Text]
  9. Pyzdrowski KL, Kendall DM, Halter JB, Nakhleh RE, Sutherland DE, Robertson RP 1992 Preserved insulin secretion and insulin independence in recipients of islet autografts [see comments]. N Engl J Med 327:220–226[Abstract]
  10. Kendall DM, Teuscher AU, Robertson RP 1997 Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes 46:23–27[Abstract]
  11. Paty BW, Ryan E, Shapiro AM, Lakey JRT, Robertson RPIntrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes, in press
  12. Gupta V, Wahoff DC, Rooney DP, Poitout V, Sutherland DE, Kendall DM, Robertson RP 1997 The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes 46:28–33[Abstract]




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