Development of a Delayed-Type Hypersensitivity (DTH) Model in the Cynomolgus Monkey.

Area of Science:

• Immunology
• Toxicology
• Primate Models

Background:

• T-dependent antibody response (TDAR) assays are standard for nonclinical immunotoxicity evaluation.
• Cell-mediated immune responses, assessed by delayed-type hypersensitivity (DTH), offer valuable complementary data.
• Assessing DTH in nonclinical settings is crucial for comprehensive immunotoxicity assessment.

Purpose of the Study:

• To evaluate the induction of a delayed-type hypersensitivity (DTH) response in Cynomolgus monkeys using tetanus toxoid.
• To establish a reliable nonclinical model for studying cell-mediated immunity.
• To compare the DTH response induced by tetanus toxoid versus Keyhole Limpet Hemocyanin (KLH).

Main Methods:

• Male Cynomolgus monkeys received intramuscular injections of Keyhole Limpet Hemocyanin (KLH) or tetanus toxoid (adjuvanted with aluminum hydroxide).
• Animals were challenged intradermally with antigens or aluminum hydroxide at 4, 6, and 8 weeks post-injection.
• Clinical reactions were scored, and skin biopsies were analyzed histologically and via immunohistochemistry (CD3, CD19, CD68).

Main Results:

• Tetanus toxoid elicited stronger clinical reactions and perivascular mononuclear cell infiltrates (consistent with DTH) compared to KLH.
• Aluminum hydroxide alone did not induce a clinical reaction or DTH.
• Immunohistochemistry confirmed the presence of T lymphocytes and macrophages within the observed infiltrates.

Conclusions:

• Tetanus toxoid adjuvanted with aluminum hydroxide reliably induces a DTH response in Cynomolgus monkeys.
• This model is suitable for evaluating cell-mediated immune responses in nonclinical immunotoxicity studies.
• DTH assays provide valuable insights into cell-mediated immunity beyond TDAR.