AutoImmune Disorders

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 TDAR   SLE


T-CELL-DEPENDENT ANTIBODY RESPONSE (TDAR)
OVERVIEW

The immune system has been identified as a target organ for adverse effects caused by test material administration. Because of this, the T-Cell-Dependent Antibody Response (TDAR) assay is used to assess potential immunotoxicity and to determine the impact of a test material on the immune response at the preclinical stage of drug discovery. This assay is the gold-standard for studying these effects due to the requirement of multiple immune functions and cell types to generate an antibody response including antigen uptake and presentation, CD4 T cell help, B cell activation and antibody production.

Biomere has validated multiple TDAR models including non-human primates and rodent models.

TDAR ASSAY ANIMAL MODELS AVAILABLE

Non-Human Primates

Rodents

TDAR ASSAY READOUTS



Female C57BL/6 mice from JAX were treated with either vehicle or anti-CD154 mAb intraperitoneally (IP) on Day -1. On Day 0, mice were given NP-KLH IP. Serum was collected from mice on Day -1, 7, and 14 and (A) anti-NP IgM and (B) anti-NP IgG ELISAs were performed.







Naïve male and female cynomolgus macaques of Chinese origin were treated with vehicle or anti-CD154 mAb IV on Day 0, 14, and 28. On Day 3 and 31, NHPs received KLH intramuscularly (IM). Serum was collected from animals twice weekly through Day 56 and (A) anti-KLH IgM and (B) anti-KLH IgG ELISAs were performed on serum samples. (C-I) Flow cytometry was performed on blood samples on Day 49. Frequency of (C) CD4+ TH cells, (D) IFNγ+ TH cells, and (E) TNFα+ TH cells. Frequency of (F) CD20+ B cells, (G) Naïve B Cells, (H) Germinal Center B Cells, and (I) Memory B Cells.

Summary

Significant decreases were observed in IgM and IgG antibodies generated in both the mouse and NHPTDAR assays in immune suppressive treatment (α-CD40L) compared to vehicle control. A proportional decrease in germinal center B cells compared to other B cell groups, as well as a decrease in B cells as a total population in α-CD40L versus control were observed. Decreases in the proportion of CD4+ TH cells were also observed in α-CD40L treated versus control, with a decrease in the proportion of IFNγ+ TH cells. From these results, we can see α-CD40L was able to suppress the generation of antibodies against the target antigen and impacted the TH cell and germinal center B cell response.


MOUSE MODELS OF SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)

NZB/W F1 MOUSE MODEL OF SLE

Characteristics

Clinical Measures

FLOW CYTOMETRY

HISTOPATHOLOGY

NZB/W F1 SLE MOUSE PREVENTION STUDY

NZB/W F1 SLE MOUSE REMISSION STUDY

Both mice reached the same humane endpoint, but lymphocyte aggregates were noticeably more severe in MRL/lpr mice (mean score = 3) compared to NZB/W F1 mice (mean score = 2)


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