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Clinical islet transplantation: advances and immunological challenges

Nature Reviews Immunology volume 4, pages 259–268 (2004)Cite this article

Key Points

  • Clinical islet allotransplantation has progressed slowly since improved islet-isolation technologies resulted in the achievement of insulin independence in the first series of successful islet allografts in 1990.

  • Insulin-independence rates have markedly improved as new and more effective combinations of immunosuppressive drugs have been introduced.

  • Because of the risks associated with life-long recipient immunosuppression, islet transplants are now limited to the most severe cases of type 1 diabetes.

  • For islet transplantation to become widely applicable, successful strategies for tolerance induction need to be developed.

Abstract

Type 1 diabetes mellitus results from autoimmune destruction of the insulin-secreting cells in the pancreas. Daily treatment with exogenous insulin is required, but because of difficulties in achieving physiological control of blood-glucose concentrations, chronic and degenerative complications still occur in a marked fraction of patients. Islet transplantation can normalize metabolic control in a way that has been virtually impossible to achieve with exogenous insulin, but life-long immunosuppression of the recipients is required, limiting the procedure to the most severe forms of diabetes. This article outlines the history of and recent progress in the field, as well as the present immunological challenges and possible strategies for tolerance induction that are crucial to make clinical islet transplantation more widely available.

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Figure 1: T-cell-growth-factor-related immunoglobulin fusion proteins.
Figure 2: Selective destruction of activated effector T cells.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health, the Juvenile Diabetes Research Foundation Center for β-Cell Replacement and Tolerance Induction at the University of Miami-Diabetes Research Institute, the Juvenile Diabetes Research Foundation-Harvard Medical School Islet Transplant Center, the American Diabetes Association and the Diabetes Research Institute Foundation.

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Authors and Affiliations

  1. University of Miami School of Medicine, Diabetes Research Institute, Miami, 33136, Florida, USA

    Camillo Ricordi

  2. Departments of Medicine and Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Terry B. Strom

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Correspondence to Camillo Ricordi.

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DATABASES

LocusLink

CD3

CD25

CD28

CD134

CD134L

CD154

CTLA4

IFN-γ

IL-2

IL-4

IL-5

IL-10

IL-12

IL-13

IL-15

FURTHER INFORMATION

Diabetes Research Institute homepage

Glossary

HYPERGLYCAEMIA

Increased plasma-glucose concentrations that are above defined normal standards.

NON-OBESE DIABETIC (NOD) MICE

A strain of mouse that normally develops idiopathic autoimmune diabetes through a disease process that closely resembles type 1 diabetes in humans. A series of pancreas islet-cell-specific target antigen(s) are recognized by pathogenic CD4+ T cells, but their identities have remained elusive.

FK506

The initial name given to tacrolimus, a metabolite of the fungus Streptomyces tsukubaensis. It is a potent immunosuppressive agent that inhibits the formation of important growth-promoting cytokines, including interleukin-2.

RAPAMYCIN

A new immunosuppressive drug that is structurally related to tacrolimus. It is produced by the organism Streptomyces hygroscopicus. It prevents the translation of mRNAs encoding cell-cycle regulators and controls progression from the G1 to S phase of the cell cycle.

CENTRAL TOLERANCE

This form of tolerance refers to the lack of self-responsiveness found as lymphoid cells develop, and is associated with the deletion of autoreactive clones. For T cells, this occurs in the thymus. Many facets of classical central tolerance are evident in mixed donor and recipient haematopoietic chimaeras that are rendered tolerant to transplanted donor tissue allografts.

PERIPHERAL TOLERANCE

Refers to the lack of responsiveness of mature lymphocytes to specific antigen. In transplant and autoimmune models, peripheral tolerance depends on active T-cell-dependent immunoregulation.

ACTIVATION-INDUCED CELL DEATH

(AICD). The apoptotic cell death of activated lymphocytes. It ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion. Defects in AICD result in lymphoproliferative diseases that are associated with autoimmune disorders.

PASSIVE CELL DEATH

The death of T cells due to activation in the absence of sufficient survival signals, or when antigen is cleared and T-cell receptor signals cease.

CYTOKINE TOXINS

Fusion proteins in which the cell-targeting sequences of diphtheria or pseudomonas exotoxin are replaced with a cytokine. The molecules are designed to target and intoxicate cells that express cytokine receptors.

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Ricordi, C., Strom, T. Clinical islet transplantation: advances and immunological challenges. Nat Rev Immunol 4, 259–268 (2004). https://doi.org/10.1038/nri1332

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