Xenotransplantation

Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research

“…Many immunosuppressive modalities in combination with various β-cell xenograft products are tested first in rodents offering a 'soft filter' of efficacy: but, these models have limited value as the situation in the rodent does not mimic the complexity of the human immune system. On the other hand, the NHP model is used to provide a higher level of stringency because the immune system in an NHP is essentially similar to that in humans so that the outcome of efficacy studies on immunosuppressive regimens is highly predictive of the human situation (Gaur, 2004;Haanstra and Jonker, 2008;Kirk, 1999;Schuurman, 2008). Note, that most human-directed biologicals show cross-reactivity to NHPs and immune monitoring can be performed like is done in humans (Chapman et al, 2007).…”

The usefulness and limitations of the diabetic macaque model in evaluating long‐term porcine islet xenograft survival

“…NHPs are most suitable in case that the intervention aims to affect the immune system as the immune system in NHPs closely resembles that in humans [reviewed in Ref. 1], most human‐directed biologicals cross‐react with NHPs, and monitoring of, for example, immune and safety parameters can be performed like this is done in humans. The value of NHP models is demonstrated by the many new IS modalities tested in life‐supporting NHP transplantation models before entering clinical development.…”

Management of adverse side-effects after chemotherapy in macaques as exemplified by streptozotocin: case studies and recommendations

“…4 The nude mouse bioassay is considered the gold standard for islet product testing as it relates to quality control, islet cell potency for product release and studies assessing refinements in islet cell processing techniques or islet cell modification during manufacturing. 4 NHPs, mostly macaques and baboons, are widely used in transplantation translation research 5,6 because of the close phylogenetic relationship to humans and development of human-like disease and symptoms. Studies in NHPs combining efficacy and safety outcomes are often needed as part of the proof-of-concept documentation supporting the phase transition into clinical explorations.…”

“…to the galactose a-1-3 galactose epitope) and show cross-reactivity with many human directed biologicals. 6 On a practical level, complex multifaceted immunological, metabolic and haematological (i.e. safety) monitoring can be performed via blood sampling and ex vivo assays that parallel clinical management.…”

“…Intensive insulin therapy can be initiated in the case of DKA (3), and corrections for electrolyte abnormalities (4) and acid/base deficit (5) can commence. Except for the most severe cases in which the animal might refuse oral fluids, administration of maintenance fluids per os is encouraged(6). This cycle is repeated until a resolution of symptoms.…”