Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: BAFF, a potent B cell survival factor, is an established therapeutic target in SLE, with the anti-BAFF antibody, belimumab, being FDA-approved for the treatment of SLE. Nevertheless, large percentages of SLE patients failed to respond to belimumab in the seminal phase-III trials, pointing to an ongoing large unmet therapeutic need. Inhibition of one or more of the individual BAFF receptors (BCMA, TACI, BR3) may, in principle, be more efficacious than global inhibition of BAFF. Indeed, whereas the contribution of BAFF to SLE has been the subject of substantial investigation, the contributions of the individual BAFF receptors to SLE have undergone only limited investigation to date. In the SLE-prone NZM 2328 (NZM) mouse model, NZM mice singly-deficient in any BAFF receptor develop clinical SLE with a time course indistinguishable from that of NZM wild-type (WT) mice, demonstrating sufficient functional redundancy among the BAFF receptors to render any single BAFF receptor dispensable to the development of SLE in these mice. To determine whether elimination of combinations of BAFF receptors could be clinically beneficial, we examined the effect of eliminating discrete pairs of BAFF receptors on the development of disease in NZM mice.
Methods: NZM mice singly-deficient in BCMA, TACI, and BR3 were intercrossed to yield NZM mice deficient two BAFF receptors (NZM.Br3-/-.Bcma-/-, NZM.Br3-/-.Taci-/-, and NZM.Bcma-/-.Taci-/-). These mice were evaluated for BAFF receptor expression and lymphocyte phenotype by flow cytometry, for renal immunopathology by immunofluorescence and histopathology, and for clinical disease by assessment of proteinuria (³3+ by dipstick) and death.
Results: The only BAFF receptor expressed by NZM.Br3-/-.Bcma-/- mice is TACI; the only BAFF receptor expressed by NZM.Br3-/-.Taci-/- mice is BCMA; and the only BAFF receptor expressed by NZM.Bcma-/-.Taci-/- mice is BR3. All B cell subsets are reduced in NZM.Br3-/-.Bcma-/- and NZM.Br3-/-.Taci-/- mice but are increased in NZM.Bcma-/-.Taci-/- mice. All T cell subsets, other than naive CD4+ cells, are reduced in NZM.Br3-/-.Taci-/- mice but are increased in NZM.Bcma-/-.Taci-/- mice. CD4+ memory cells are reduced in NZM.Br3-/-.Bcma-/- mice. Renal immunopathology and clinical disease are significantly delayed and attenuated in NZM.Br3-/-.Bcma-/- and NZM.Br3-/-.Taci-/- mice but are significantly accelerated in NZM.Bcma-/-.Taci-/- mice (Figure 1).
Conclusion: Elimination of both BR3 and TACI (while retaining BCMA) or both BR3 and BCMA (while retaining TACI) markedly inhibits development of SLE in NZM mice. By extension, selective pharmacologic targeting of BR3 + TACI (while preserving BCMA engagement) or BR3 + BCMA (while preserving TACI engagement) may represent a successful therapeutic approach in human SLE.
C. O. Jacob,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/amelioration-of-systemic-lupus-erythematosus-sle-in-nzm-2328-mice-by-selectively-blocking-engagement-of-two-baff-receptors/