Page 115 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Experimental Autoimmune Vasculitis 91

These findings suggested that there were protective mechanisms operating in immunized
NOD mice mediated by regulatory lymphocyte populations, while the genetic background
and degree of immunodeficiency appeared to play an important role in disease susceptibility.
In the successful anti-MPO splenocyte transfer model of Xiao et al. [5], the recipient strain
was C57BL/6-RAG2-/- further underscoring the difference between MPO and PR3 immunity.
The presence of glomerular immune deposits was not discussed in the report by Primo and
colleagues [25]. Their results were of limited applicability to human anti-PR3 associated
AAV. Relle and colleagues [26] successfully created transgenic FVB mice that expressed
human PR3 into which they infused monoclonal anti-PR3 antibodies.

However, expression of PR3 was under the control of the podocin promoter meaning that
protein was expressed only in glomeruli. Not surprisingly, they [26] did not detect any
pathological features of vasculitis as the current AAV paradigm for pathogenesis proposes
interaction of the antibody with PR3 on neutrophils and monocytes, not glomerular cells, with
resultant activation of these cells and bystander microvascular injury.

One hallmark of ANCA vasculitis is that the glomerular lesions are pauci-immune,
meaning that there is little or no local glomerular immune complex formation. One wonders
whether different results would have been obtained if human PR3 had been expressed on the
surface of myeloid cells, although it is likely that one would need to link it to other membrane
bound proteins such as CD177 to see the intracellular effect of ANCA binding.

Little and co-workers [27] recently described the use of humanized immunodeficient
NOD SCID IL2-receptor knockout mice, which received human hematopoetic stem cells and
developed a human-mouse chimeric immune system. These mice developed mild
glomerulonephritis and lung hemorrhage without evidence of granulomata following passive
transfer of PR3-ANCA containing IgG derived from patients with severe systemic vasculitis.

These exciting developments open the way for further investigation of pathogenic
mechanisms and definition of immune requirements for the induction of anti-PR3 associated
vasculitis.

Conclusion

By inducing an abnormal immune response to MPO, investigators have succeeded in
generating pathological changes in mice and rats that mimic human MPO-ANCA-AVV,
although most models exhibit much milder disease than that usually seen in patients. Passive
transfer of pathogenic antibody has proven a useful tool for investigating the molecular
mechanisms underlying acute vascular injury, and supports the concept that anti-MPO
antibodies, in conjunction with neutrophils, are capable of inducing such injury.

This provides a rationale in support of therapeutic strategies that aim to remove these
antibodies, such as plasma exchange and rituximab.

Active immunization of mice and rats with MPO has provided a more accurate model of
an immune response that involves both cellular and humoral immunity allowing investigation
of the role of T-cells, specifically those of the Th17 axis that have been implicated in
autoimmune disease. Such active immunization strategies are well suited to long term
therapeutic trials of novel agents, although for this to be truly useful, the disease phenotypes
of the particular models will need to be more severe.

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