Page 112 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

88 Alan D. Salama and Mark A. Little

lack of clinical evidence of complement consumption in AAV. Since the available small
molecule inhibitors of C5a receptor were only active against the human form of the receptor,
Xiao and colleagues [10] adapted the murine anti-MPO transfer model by generating mice
transgenic for the human C5a receptor allowing them to test the inhibitor in the murine model
and demonstrate its efficacy in reducing renal disease.

A subsequent human trial using this C5a receptor antagonist in treatment of AAV was
initiated [11]. Further modifications of this model used a bone marrow transplant approach in
which immunization of MPO-deficient mice with murine MPO, were subjected to lethal
irradiation followed by transfer of either MPO-expressing or MPO-deficient bone marrow.

MPO expression on hematopoetic cells was necessary for disease induction [12], as only
transfer of MPO-sufficient cells resulted in disease manifested as necrotizing
glomerulonephritis. With various refinements, this model [5] revolutionised the
understanding of the mechanisms of acute anti-MPO induced vascular injury. However, all of
the model variations had limitations as these were not autoimmune in nature, but relied
instead on alloimmune responses to MPO. Comparisons of the avidity of alloimmune anti-
MPO antibodies and other autoimmune ones formed by immunizing WT mice with MPO
have not been reported, although it is suspected that there would be significant differences
reflecting the propensity for disease induction with this model compared to previous failed
attempts by direct MPO immunization. Furthermore, as with all induced models, they begin
downstream of the break in clinical immune tolerance with a pre-formed anti-MPO antibody,
restricting some of the potential insights into clinical disease initiation. A slightly different
strategy for modelling MPO autoimmunity was adopted by Ruth and co-workers [13]. The
investigators [13] immunized C57BL/6 mice with MPO in adjuvant, both human and murine,
generating cellular and humoral anti-MPO responses, followed by low dose sub-
nephritogenic nephrotoxic serum to induce a local renal immune response within glomeruli.
In contrast to the passive MPO model, this technique depended upon T-cell and not B-cell
immunity. Effector CD4+ cell depletion attenuated crescentic glomerulonephritis and effector
cell influx without altering ANCA titers. However, B cell-deficient mice, with no ANCA, still
developed severe crescentic glomerulonephritis with accumulation of effector cells [13]. The
proposed explanation of the model was that it relied upon deposition of MPO in the
glomerular circulation following neutrophil migration and de-granulation in response to
deposited nephrotoxic serum. There was in turn a subsequent adaptive cellular immune
response towards the deposited MPO already induced by the prior immunization of MPO in
adjuvant. This model was used by Gan and colleagues [14] to illustrate the importance of the
key Th17 effector cytokine IL-17A. To test whether IL-17A also drives autoimmune delayed-
type hypersensitivity in the kidney, the investigators [14] injected MPO into the kidneys of
MPO-sensitized mice noting that IL-17A deficiency reduced accumulation of renal
macrophages and renal CCL5 mRNA expression, lending support to the clinical findings of
elevated IL-17 levels in patients with acute and more severe disease in AAV [15]. This model
also demonstrated the importance of innate immune pathway stimulation as a co-stimulus for
disease induction as well as the pathogenic role of TLR in initiating autoimmune AAV in a
series of experiments in which TLR-2 induced Th17 CD4 cells while TLR-9 directed
vasculitis by enhanced Th1 autoimmunity [16]. These observations were likely due in part to
the mimicking influence of infection and TLR signalling on development of ANCA
autoimmunity and organ related disease leading to glomerulonephritis.

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