INFLAMMATION AND IMMUNE DISEASE MODELS

Rigorous inflammation and immune disease NHP models.

In 2008, the mummy of king Mernepath, an egyptian pharaoh who ruled over Egypt some 3,200 years ago was put under investigation along with other mummies to confirm their cause of death, which was hypothesized to be atherosclerosis. Surprisingly, all mummies showed fatty buildups in their arteries. Atherosclerosis, an inflammatory disease affecting 101 in 1000, was always thought to be caused by modern lifestyles: smoking, diabetes, a sedentary lifestyle, etc., none of which were prevalent 3,200 years ago.

If there is one thing the scientific method has taught us at PharmaLegacy, it’s skepticism. Some inflammatory and immune diseases have been described in the literature for ages, long before NHP models were developed. Yet sometimes, mummies that were left untouched for thousands of years prove to us that we should always remain skeptical: nothing is written in stone in science. Whether you are trying to bolster established literature, or challenge what was once thought to be written in stone, PharmaLegacy has your back!

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Inflammation, Immune & Autoimmune Diseases

MODELS / SERVICES

Case Study:TTx-Induced DTH in Cynomolgus Monkey

Animal: Cynomolgus monkeys, 2.5 – 3.3 kg

Material: Tetanus Toxoid (TTx) Vaccine

DTH Response in Cynomolgus Monkey

DTH expressed as skin induration on the challenged spots and treatment with topical Dex or systemic cmpd-X attenuated this response.

Skin Erythema, Edema, Indurations

Skin Histopathology Evaluation

IHC: Immune Cell Infiltrate Determination: Examination

Monocytes, B &T Cells, and NK Cells in Peripheral Blood

Similar to Dexamethasone, the cmpd-X treatment group showed a decrease in CD14+ monocyte and classical monocyte (CD14+CD16-). However, levels of activated monocyte (CD14+CD16+) and other major immune cell populations, e.g. B cells, T cells, NK cells, were not affected as compared to vehicle group.

Case Study:Chemotherapy-Induced Mucositis in Cynomolgus Monkey

Animal: Cynomolgus monkeys, female

Material: Irinotecan (CPT-11)

Mucositis: Inflammation and Ulceration of The SI

Clinical Assessment of Mucositis

White Blood Cell (WBC) and Differential Counts

Similar to the decrease of WBC counts after CPT-11 challenge, Lymph#, Neu# and Eos# were also declined. ~12 days later, these cells went back to their baseline.

Villi shortening, crypt destruction, and impaired goblet cell mucin production was observed in the model.

DSS-Induced Colitis in Cynomolgus Monkey

Animal: Cynomolgus monkeys, male

Material: : DSS (Dextran sulfate sodium)

Clinical Readouts of A Small Case (n=2 for Each Group)


Colonic Histopathology

Scoring System for Tissue Damage

Blood Cell Counts

Whole Blood Cell Counts Demonstrated:

• Up-Regulated Activity of Innate Immune Response:

Increased number of phagocytes (monocytes and neutrophils), which can be accounted by the defective intestinal barrier and microbial infection after DSS challenge.

• Slight Anemia:

RBC& HGB drop was in line with the intestinal bleeding since Day7.

• Rising Platelet Count

A possible compensatory response to counteract intestinal bleeding.

Clinical Signs

Summary:

• Progressive development: reduced food intake, body weight loss, diarrheal, hemoccult and rectal bleeding.

• Abnormal signs in gross anatomy were largely restricted to colon.

• Shortening of colon length, increasing in colon thickness, colon ulceration and bleeding, epithelial erosion and shedding, enlargement of mesenteric lymph nodes

• Considerable Reproducibility

Collagen II-Induced Arthritis (CIA) in Cynomolgus Monkey

Results: mRNA profile in CIA monkey

Results: Blood biomarkers in CIA monkey

Hematocrit and Hemoglobin vs. Arthritic Score-Anemia Association

Effects of Anti-Human IL-6 Monoclonal Antibody on CIA in Female Cynomolgus Monkeys

Results: X-Ray Score

Effects of IL-6 Receptor Blocker on CIA in Female Cynomolgus Monkeys

Results: X-Ray Score


Results: PIP histopathology evaluation (toluidine blue staining)

I.V. LPS-Induced Cytokines Production in Cynomolgus Monkey

Animal: Cynomolgus monkeys, male

Material: Lipopolysaccharide (LPS)

Case Study:LPS-Induced Systemic Inflammation Model

Animal: Cynomolgus monkeys, male

Material: Lipopolysaccharide (LPS)

In-Life Clinical Observations


Serum Biochemistry


Coagulation Indicators


Complete Blood Count (CBC) (I)


Complete Blood Count (CBC) (I)

In-life observation showed that all animals treated with LPS endotoxin developed extensive symptoms including loss of appetite, insensitiveness, excessive fatigue and apathy. All the clinical observation signs demonstrated the systematic inflammation was successfully induced by LPS infusion including high body temperature, increased heart rate and decreased SpO2.

LPS induced liver and kidney function impairments in all animals were reflected by increased serum levels of ALT, AST and BUN.

Following LPS infusion, APTT and PT showed delay in time at all time points measured in blood plasma compared to the baseline (heathy status). Fibrinogen levels increased continuously starting 12 hours after LPS administration in both groups.

Case Study: Anti-inflammatory activity of the bradykinin B1R antagonist in a model of LPS-induced lung inflammation in the cynomolgus monkey

At 12h post LPS challenge, BAL cells were significantly elevated (p < 0.05) over baseline (LPS: 20 x 106 vs naive: 2 x 106) which was mainly due to an accumulation of neutrophils (LPS: 80 % vs naive: 1.5 %). BALF protein was significantly increased (p < 0.05) 12 h after LPS challenge (LPS: 3 mg/ml vs naive: 0.9 mg/ml). Of all the cytokines measured, only BALF IL-8 was significantly increased (p < 0.05) 12 h after LPS challenge (LPS: 1100 pg/ml vs naive: 200 pg/ml).

The number of neutrophils and other inflammatory parameters returned to baseline level one week after LPS challenge. All treatments, B1R antagonist, PDE4 inhibitor and dexamethasone, significantly reduced (p < 0.05) LPS-induced BAL neutrophilia (~80 % inhibition) and BALF protein (~90 % inhibition). The B1R-antagonist inhibited BALF IL-8 by 50 %, dexamethasone by 80 % and the PDE4 inhibitor by 100%.

These data show that a cross-over design in the model of LPS-induced lung inflammation in the cynomolgus monkey is meaningful because all inflammatory parameters returned to baseline one week after LPS challenge. In this study the B1R antagonist displayed an anti-inflammatory activity similar to dexamethasone and the PDE4 inhibitor.

Cytokine responses in LPS-induced lung inflammation model:

More data about the LPS-induced lung inflammation model Cytokines in BALF:

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