DOI: 10.5061/dryad.99fq552
title: Data from: BLT-immune humanized mice as a model for nivolumab induced immune-mediated adverse events: Comparison of the NOG and NOG-EXL strains

description: Checkpoint inhibitors represent a new class of therapeutics in the
 treatment of cancer that have demonstrated remarkable clinical
 effectiveness. However, some patients have experienced serious
 immune-mediated adverse effects including pneumonitis, hepatitis, colitis,
 nephritis, dermatitis, encephalitis, and adrenal or pituitary
 insufficiency. These adverse events were not predicted by nonclinical
 studies. To determine if bone marrow-liver-thymus (BLT) immune humanized
 mice could demonstrate these adverse effects, we studied the effect of
 nivolumab on two strains of BLT-humanized mice, NOD.Cg-Prkdcscid
 Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug
 Tg(SV40/HTLV-IL3,CSF2)10-7Jic/JicTac (NOG-EXL). Mice were treated with
 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days.
 BLT-NOG mice had significantly reduced survival compared to BLT-NOG-EXL
 mice. In spite of the difference in survival, both BLT-humanized strains
 showed adverse reactions similar to those reported in humans, including
 pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also
 noted in some individuals. Additional histopathologic findings included
 pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell
 activation increased with concomitant loss of PD-1 detection. These
 findings show that BLT immune humanized mice can demonstrate
 immune-mediated adverse effects of anti-PD1 therapy, and may represent a
 model that can be used to better understand toxicity of this class of
 drugs.
description: Suppl Table
 1Summary of
 histopathologic findings for each animal.Supplemental Figure
 1Supplemental Figure 1:
 Spleen and submandibular lymph node pathology. Splenic (left panel) and
 lymph node (right panel) sections considered to have normal parenchymal
 architecture from a saline control BLT-NOG mouse are shown in A and B
 respectively. In BLT-NOG (C) and BLT-NOG-EXL (E) nivolumab treated mice,
 multifocal, pale, expansile nodules composed mainly of histiocytes
 (insets) were observed. Similarly, lymph nodes in the BLT-NOG (D) and
 BLT-NOG-EXL (E) treated groups exhibited histiocytic nodular infiltrates
 (high magnification insets) that were slightly more eosinophilic.
 Hematoxylin and eosin.Supplemental Figure
 2Supplemental Figure 2:
 Pathology of less common histological findings in BLT-NOG and BLT-NOG-EXL
 nivolumab treated mice. Lesions observed in both BLT-NOG and BLT-NOG-EXL
 treated mice included submucosal lymphohistiocytic infiltrates in the
 stomach (A), often at the region of the limiting ridge, and; regionally
 extensive, mural to transmural lymphohistiocytic and neutrophilic
 infiltrates in the cecum (B). Lesions limited to BLT-NOG-EXL nivolumab
 treated mice included multifocal lymphocytic (and fewer histiocytic)
 infiltrates in the urinary bladder submucosa (C); mild, regionally
 extensive lymphocytic meningitis at the level of the diencephalon (D),
 and; multifocal lymphohistiocytic and occasionally neutrophilic
 infiltrates extending into the trigeminal nerve and ganglia (E), and the
 pituitary gland (F). Hematoxylin and eosin.Supplemental Figure
 3Supplemental Figure 3:
 Representative histological figures from a mouse with graft versus host
 disease. GvHD inflammatory lesions in skin (A), lung (B), liver (C),
 kidney (D), pancreas (E), and sternum (F) are considered less severe,
 segmental to multifocal rather than more diffuse, and consist of more
 lymphocytes than histiocytes (insets) with fewer instances of granulomas
 compared to nivolumab treated BLT-NOG and BLT-NOG-EXL mice. Hematoxylin
 and eosin.