Share this article on:

Subcutaneous Islet Allotransplantation Without Immunosuppression Therapy: The Dream of the Diabetologists and of Their Patients

Bertuzzi, Federico MD1; De Carlis, Luciano Gregorio MD2

doi: 10.1097/TP.0000000000001947
Commentaries

1 Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

2 Surgical and Transplant Department, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Received 8 August 2017.

Accepted 4 September 2017.

The authors declare no funding or conflicts of interest.

F.B. wrote the article, L.D.C. contributed to discussion.

Correspondence: Federico Bertuzzi, MD, Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, P.zza Ospedale Maggiore 3, 20162 Milan, Italy. (federico.bertuzzi@ospedaleniguarda.it).

First islet transplantation in patients affected by type 1 diabetes mellitus occurred in the years 1989 to 1990.1 Since these first cases, more than 1000 islet transplantations have been done with a progressively increased successful rate. However, in more than 25 years, this approach remains available only for a few selected patients with brittle diabetes and not for most of the patients, especially the youngest ones. Three major problems still occur: poor islet availability, long term poor graft function, and the need of immunosuppression therapy.

Many solutions and many strategies have been proposed in the years.2 The bottlenecks for most of the proposed solutions appear to be related to the choice of the liver as the site of implant. The liver still represents the standard site for islet transplantation, which has been the only site associated with successful islet transplantation. However, some limits of the islet transplantation that has obstructed a real development of this approach has appeared to be strictly connected to the liver: poor islet engraftment due to the instant blood-mediated inflammatory reaction, impossibility of adapting local immunomodulatory/immunoprotection strategies, chronic islet exhaustion due to glucotoxicity, in portal vein high concentrations of drugs that are toxic for beta cells and the limited space available for the islet graft. The transplantation of beta cells achieved by stem cells is not feasible in the liver. These cells cannot be physically isolated from the liver and cannot be retrieved, unless they have unwanted effects.

Recently, different clinical trials have commenced, trying to transplant pancreatic islets in other sites, as intramuscle,3 into bone marrow4 and on omentum with initial promising results only for omentum.5 The subcutaneous space appears as the most interesting site for islet transplantation, an alternative to the liver, mainly for the easy access, easy visualization of the graft, and because it allows local immunosuppressive/immunomodulatory strategies and the transplant of large volume of tissue.6 In the subcutaneous tissue, the transplanted cells can be physically isolated by tissue engineering strategies and retrieved, if it is needed. However, the vascularization and local oxygenation is lower than expected for proper islet engraftment, especially in the early period after transplantation. Many protocols in animal models of islet transplantation have been proposed to promote local vascularization into the subcutaneous tissue with successful results.7,8 In addition, many strategies have been proposed to protect the islet from rejection by tissue engineering technique and capsulation. All these strategies required proper validation, authorization as cell therapy before moving in clinical trial. This probably is one of the reasons why clinical trial of islet transplantation into the subcutaneous tissue has not been started yet.

Probably, this is the right time for a new approach and a new strategy.

Recently, in a diabetic rat model, L.N.M. and I.H. have shown that allogeneic islets transplanted in a subcutaneous site prevascularized with agarose-fibroblast growth factor-2 and heparin can restore normoglycemia for a long period without immunosuppressive therapy.9 In the same direction, the article of Iwata et al from the same University in the current volume of Transplantation confirms the possibility of achieving normoglycemia by subcutaneous allotransplantation in a mice model without immunosuppression using a different molecule.10 The authors applied an agarose rod containing the cyclic oligopeptide SEK-1005 that induced local vascularization and led to the formation of granulomatous tissue containing regulatory T cells that suppressed immune reactions. The inflammatory reaction seems to contribute to host inflammatory cell recruitment and neovascularization by a mechanism that involves TGF-β1 production. The released TGF-β1 plays an important role in the formation of highly vascularized and immune tolerant granulomatous tissue.

It is unlikely that systemic tolerance was induced because the graft rejection occurred after a subsequent injection of donor-antigens and therefore some immunological issues have to be further clarified. The evidence that the same results can be achieved by 2 similar approaches with 2 different molecules, agarose-fibroblast growth factor-2 and heparin,9 and SEK-100510 is intriguing and deserves further analyses. The analyses of the maximal number of islets that can be transplanted in a single pocket created by the agarose rod are not performed. Finally, the literature has largely shown that most of the strategies for successful islet transplantation in mice gave disappointing results when the protocol was applied to humans.

However, the combination of the simplicity of this approach as well as the possibility of avoiding immunosuppression therapy represents a strong reason to plan a project toward a clinical trial starting from the data of Iwata.10 The idea that a minimal surgical procedure in local anesthesia might restore normoglycemia in patients affected by type 1 diabetes mellitus without immunosuppression therapy represents a great advance in the field of islet transplantation and the real dream of diabetologists and of their patients.

Back to Top | Article Outline

REFERENCES

1. Piemonti L, Pileggi A. 25 years of the Ricordi automated methods for islet isolation. CellR4. 2013;1:e128.
2. Bruni A, Gala-Lopez B, Pepper AR, et al. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab Syndr Obes. 2014;7:211–223.
3. Christoffersson G, Henriksnas J, Johansson L, et al. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes. 2010;59:2569–2578.
4. Cantarelli E, Melzi R, Mercalli A, et al. Bone marrow as an alternative site for islet transplantation. Blood. 2009;114:4566–4574.
5. Baidal DA, Ricordi C, Berman DM, et al. Bioengineering of an intraabdominal endocrine pancreas. N Engl J Med. 2017;376:1887–1889.
6. Sakata N, Aoki T, Yoshimatsu G, et al. Strategy for clinical setting in intramuscular and subcutaneous islet transplantation. Diabetes Metab Res Rev. 2014;30:1–10.
7. Pepper AR, Gala-Lopez B, Pawlick R, et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015;33:518–523.
8. Pepper AR, Gala-Lopez B, Ziff O, et al. Revascularization of transplanted pancreatic islets and role of the transplantation site. Clin Dev Immunol. 2013;2013:352315.
9. Luan NM, Iwata H. Long-term allogeneic islet graft survival in prevascularized subcutaneous sites without immunosuppressive treatment. Am J Transplant. 2014;14:1533–1542.
10. Kuwabara R, Hamaguchi M, Fukuda T, et al. Long-term functioning of allogeneic islets in subcutaneous tissue pretreated with a novel cyclic peptide without immunosuppressive medication. Transplantation. 2018;102:417–425.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.