Diabetes Volume 65, March 2016 545

Bart O. Roep

Insulitis Revisited

Diabetes 2016;65:545–547 | DOI: 10.2337/dbi15-0040

Restricted access to the inflammatory lesions in patients islet-specific autoreactive CD8+ T cells in destructive insu- with type 1 diabetes (T1D) has slowed insight into human litic lesions, which supports the concept of an autoim- insulitis. The conception of a network collecting pan- mune nature of T1D. Other seminal lessons include the creases of donors with diabetes (Network for Pancreatic persistence of b-cells, insulin production, and insulitic Organ Donors with Diabetes [nPOD]; www.jdrfnpod.org) lesions that endure many years following the clinical man- has focused the international diabetes research commu- ifestation of hyperglycemia. We have learned that there is nity on islet inflammation in new tissue for the first time an apparent disconnect between b-cell mass and function in decades, leading to an overhaul in insight in human (b-cell quiescence or hibernation), that there is a pro- insulitis. In this issue of Diabetes, Campbell-Thompson found difference in the immunopathology between men et al. (1) present the latest status of insulitis in relation and mice, and that there exists an overwhelming hetero- to b-cell mass, serving the diabetes research community geneity in the pathologic lesions (varying from no in- some unexpected findings. The investigators studied the filtrate to “pauci”-autoimmune to “fulminant”)ofthis frequency and composition of insulitis in relation to b-cell patient population. nPOD has also led to the demonstra- mass throughout the natural history of T1D, i.e., from tion of focal disease activity, similar to vitiligo or alopecia, COMMENTARY seropositive donors without diabetes to donors with newly and the persistence of b-cell mass and function long diagnosed and long-standing disease. Insulitis in donors with after manifestation of hyperglycemia (2–4). The latter islet autoantibodies was rare (none of the 13 donors with a was recently appreciated again by the findings in Exeter single antibody, 2 out of 5 with multiple antibodies, with of C-peptide in the urine of the vast majority of T1D the proportion of inflamed islets ranging from 1.4 to patients, in spite of disease duration for decades (3). Al- 6.4%), whereas a large proportion of patients with long- though some of the findings presented by Campbell- lasting disease lacked islet autoantibodies, even if insulitis Thompson et al. (1) have been reported anecdotally before, persisted. The few donors with recent-onset T1D all showed the mere large sample size in the study alone deserves insulitis; in those individuals with established disease, the credit and adds value (2,5–7). Given this is work in progress, frequency of insulitis in both individual islets and within corroboration with new pancreas tissue is essential. The patients was less, irrespective of the age of disease onset. term “confirmation” does not do sufficient justice to the Therateofinsulitisremainsgreatestinisletspro- studies presented here, and many more studies and reports ducing insulin compared with insulin-negative islets on many more tissues are warranted for common themes to (33% vs. 2%), suggesting this inflammatory process is emerge and be validated. driven by the presence of b-cells. Residual b-cells per- At the same time, several issues need reconciliation. sisted in all T1D donors with insulitis, and b-cell area The study by Campbell-Thompson et al. (1) is descriptive and mass were significantly higher in T1D donors with and cross-sectional, precluding firm conclusions on changes insulitis compared with those without insulitis. The de- in time throughout disease progression. It should also be gree of heterogeneity in the numbers of inflamed islets, appreciated that the tissues investigated were derived the rate and composition of insulitis, and the remaining from autopsy, not biopsy. Indeed, subtle differences in b-cell mass within a tissue and between T1D patients the patterns of infiltration between living and dying was overwhelming. donors may emerge, e.g., leukocyte infiltration of the In its relatively short existence, nPOD has changed the exocrine pancreas increases with the time a donor spent landscape and paradigms of T1D. Recent lessons from in an intensive care unit (2,8). Although the number of nPOD’s tissue platform include the demonstration of donors and pancreas sections investigated is impressive,

Department of Immunohematology and Blood Transfusion, Leiden University © 2016 by the American Diabetes Association. Readers may use this article as Medical Center, Leiden, the Netherlands, and Department of Diabetes Immunol- long as the work is properly cited, the use is educational and not for profit, and ogy, Diabetes & Metabolism Research Institute, Beckman Research Institute of the work is not altered. City of Hope, Duarte, CA See accompanying article, p. 719. Corresponding author: Bart O. Roep, [email protected] or [email protected]. 546 Commentary Diabetes Volume 65, March 2016

Figure 1—Insulitis in the natural history of T1D. Insulitis remains undetectable unless multiple islet autoantibodies (Abs) are present in serum, albeit in a limited number of islets. The rate and diversity of insulitis seem greatest around diagnosis and are less frequent and profound in patients with long-lasting disease. Even in end-stage disease, some apparently unaffected islets and b-cells and insulitis can remain. This graphical representation does not reflect frequencies of insulitis patterns. Variations in the composition and frequency between T1D patients exist at any stage of disease. Red and orange cells represent different subsets of islet-infiltrating leukocytes.

the number of newly diagnosed donors or donors without therapy for the T1D patient community at large. Instead, diabetes with multiple islet autoantibodies in particular disease differentiation and fine diagnosis may move im- remains limited. The sample size also impairs interpreting munotherapy to precision and personalized medicine disease variation relative to ethnicity, age, disease dura- (10,11). The persistence of both b-cells and insulitis tion, and HLA polymorphisms, despite several observa- mayhelpexplainwhyabataceptmaystillworkatthe tions that hint at linked diversity (e.g., low insulitis supposedly late stage of clinical diagnosis or perhaps frequency in African American donors). Finally, the loss explain subgroup (in)efficacies (e.g., apparent lack of ef- of insulin in islets does not necessarily mean the loss of ficacy of abatacept in African American patients) (12). b-cells, as b-cells may be degranulated or progressing to- The disconnect between b-cell mass and function may ward dedifferentiation, which may confound an accurate have consequences for stimulated C-peptide as primary determination of b-cell mass. end points of immunotherapeutic efficacy, as any bene- Collectively, these new insights have set the stage for ficial therapeutic impact on insulitis may remain unno- new therapeutic strategies that may prove effective in ticed. Insulitis may require different types of therapeutic protecting b-cells long after the clinical onset of T1D. strategies than reengaging hibernating b-cells. Decrypting human insulitis may help us to understand The journey has been short so far, and beyond doubt, the differences in the efficacy of immune intervention there are many additional secrets waiting to be revealed by strategies between mice and men, as human insulitis dif- investigating diabetic tissue. There is a huge demand for more fers substantially from that in preclinical models in terms tissue and for more sharing to guide discoveries of immune fi of severity, the apparent lack of regulatory T cells, the correlates to disease progression and to nd targets for frequency of islet infiltration, and the composition of therapeutic intervention. Joint investigations of diabetic tissue the infiltrate (proportion of CD8+ vs. CD4+ T cells). This by different laboratories and experts, coupled with this unique awareness should improve the guidance of preclinical dis- data repository, will provide the basis to crack the codes of ease models into clinical translation (9). human insulitis and design immunotherapy accordingly. The new observations in human insulitis and the heterogeneity thereof create several opportunities for Funding. This work was partially funded by Diabetes Fonds, Stichting future studies. All different stages of disease appear Diabetes Onderzoek Nederland, European Union-Seventh Framework Programme present in a single pancreas, from apparently healthy islets for Research, and JDRF. through inflamed to the end stage of b-cell–depleted islets Duality of Interest. No potential conflicts of interest relevant to this article without inflammation (Fig. 1). The variation between pan- were reported. creases also bears implications for therapy. First, given the References huge degree of variation in immunopathology, no single 1. Campbell-Thompson M, Fu A, Kaddis JS, et al. Insulitis and b-cell mass in bullet is to be expected as a viable immune intervention the natural history of type 1 diabetes. Diabetes 2016;65:719–731 diabetes.diabetesjournals.org Roep 547

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