MD ThesisTubulointerstitial inflammation and fibrosis is frequently seen in patients with
progressive renal failure, irrespective of the aetiology, and may represent a common
pathway to renal failure. However, the role and function of tubulointerstitial
lymphocytes in the pathogenesis of renal fibrosis is unknown. Using the wellcharacterised
mouse model of unilateral ureteric obstruction (UUO) I determined the
phenotype of infiltrating lymphocytes and by sequencing the complementaritydetermining
region 3 (CDR3) of the variable β-chain examined whether there were
clonal populations of T cells within UUO and normal kidney.
There was a strong correlation between lymphocyte infiltration and tubulointerstitial
expansion, α-SMA staining and collagen I deposition. A population of these infiltrating
CD4+ and CD8+ lymphocytes also displayed the surface makers CD69 and CD44, and
the nuclear proliferation marker Ki67. This suggests activation and proliferation of T
cells in response to self-antigen recognition and the loss of immunological tolerance.
Infiltrating T cells within UUO kidney demonstrated over expression of certain TRVβ
gene segments in particular TRVβ3, suggesting a clonal population of lymphocytes. In
normal and sham operated kidney over expression of T cells with the TRVβ13.2, 29 and
1 gene segments suggested populations of resident NKT cells expressing an invariant T
cell receptor.
On sequence analysis of the CDR3 region of infiltrating lymphocytes, large clonal
populations of T cells were seen in individual UUO kidneys at 7 and 14 days after
obstruction but not 28 days. These clonal populations in UUO kidney that were also in
normal kidney had an identical amino acid motif within the CDR3 region. This suggests
a population of T cells in normal kidney proliferate in response to injury.
These lymphocytes could be a potential target for therapeutic interventions to prevent
fibrosis in renal diseases that are not characteristically believed to be immune mediated.The Northern Kidney Research Fund
