Implanted islets in the anterior chamber of the eye are prone to autoimmune attack in a mouse model of diabetes

Abstract

Aims/hypothesis Type 1 diabetes is an autoimmune disease resulting from the destruction of insulin-producing beta cells. Along with advances in generating replacement beta cells for treating diabetes, there is also increasing demand for non-invasive tools to evaluate the recurrence of autoimmune attack on transplanted tissue. Here, we examined the anterior chamber of the eye as a potential islet transplant site, and also evaluated whether in vivo imaging of the islets transplanted in the eye could enable real-time visualisation of autoimmune processes underway in the pancreas. Methods Syngeneic islet equivalents were transplanted into the eye or kidney capsule of streptozotocin-induced diabetic C57BL/6 mice to compare islet dose (25-125 islet equivalents) and function across transplant sites. Autoimmune attack of syngeneic islets was evaluated in the pancreas and eye tissues of NOD and NOD-severe combined immunodeficient (SCID) mice given diabetogenic splenocytes. Results Islet transplantation in the eye decreased fasting plasma glucose levels and increased weight gain and survival in an islet-dose-dependent manner. Even 50 islets in the eye reduced blood glucose levels, whereas ≥200 islets were required in the kidney for a similar effect. Autoimmune destruction of pancreatic islets in the eye mirrored that in the pancreas and could be visualised in real time by noninvasive imaging. Conclusions/interpretation We found that far fewer islets were required to restore normoglycaemia when transplanted into the anterior chamber of the eye vs the kidney capsule. However, our results suggest that islets are not protected against autoimmune attack in the eye, making this a suitable site for visualising autoimmune processes against transplanted tissue.

Antigen Recognition in the Islets Changes with Progression of Autoimmune Islet Infiltration

“…Intra-vital islet imaging has been used to demonstrate the distinct morphology of the islet vasculature and analyze blood flow rate within the islets 13 . Using a transplant model in the anterior chamber of the eye, toxin-induced β-cell death 14 , the dynamics of T cell mediated graft rejection 15 , and autoimmune attack of islet transplants 16 have been analyzed. A virally induced diabetes model was used to examine the autoimmune response within the pancreas through analysis of CD8 T cell motility and interactions with β-cells 17 .…”

Noninvasivein vivoimaging of embryonic β-cell development in the anterior chamber of the eye

“…While previous publications have indicated a risk of autoimmune attacks for islets implanted in the AC of the eye, 36 a Hematoxylin with a light Eosin stain demonstrates the absence of proinflammatory neutrophil or eosinophil (plurilobed), or lymphocytes (dark nucleus, low nuclear/cytoplasmic ratio and blue cytoplasm) infiltration ( (Fig. 3F).…”

Spleen, as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells

“…We would define it by the following three criteria: 1) sites with an abundant, oxygen-and nutrient-rich blood flow, 2) sites that are privileged immunologically to minimize transplant graft loss, and 3) sites where transplantation can be performed with minimum invasiveness. To date, many organs have been assessed including the liver [21][22][23], renal subcapsular space [21,22], omental pouch [24,25], mesentery [26], gastrointestinal tract [27], skeletal muscle [28], subcutaneous tissue [28], eye [29], brain [30], testis [31,32], bone marrow [33], thymus [34], and spleen [35]. However, it has been difficult to find a site that meets all three criteria (Table 1).…”

“…Hedger further revealed that rodent testes contain significant numbers of immunoregulatory cells, including Tregs [66]. And recently, Farooq showed that Tregs contribute to immune tolerance in the rodent anterior chamber when challenged by myelin antigen [29,30,32,34], little has been done in a human clinical setting. In particular, the brain or eye is problematic site for transplantation, as it would be difficult to remove a graft without damage in case of graft failure.…”