Heterogeneity in the Evolution and Mechanisms of the Lesions of Kidney Allograft Rejection in Mice

Abstract

The natural history and pathogenesis of the pathologic lesions that define rejection of kidney transplants have not been well characterized. We studied the evolution of the pathology of rejection in mouse kidney allografts, using four strain combinations across full major histocompatibility complex (MHC) plus nonMHC disparities, to permit more general conclusions. Interstitial infiltrate, MHC induction, and venulitis appeared by day 5, peaked at day 7-10, then stabilized or regressed by day 21. In contrast, tubulitis, arteritis, and glomerulitis were absent or mild at days 5 and 7, but progressed through day 21, indicating separate regulation and homeostatic control of these lesions. Edema, hemorrhage, and necrosis also increased through day 21. All lesions were T-dependent, failing to develop in T-cell-deficient hosts. Allografts into immunoglobulindeficient hosts manifested typical infiltration, MHC induction, and tubulitis at days 7 and 21, indicating that these lesions are alloantibody-independent. However at day 21 kidneys rejecting in immunoglobulindeficient hosts showed decreased edema, arteritis, venulitis, and necrosis.Thus the three groups of lesions are: T-cell-mediated interstitial infiltration, MHC induction, and venulitis, which develops rapidly then stabilizes; slower but progressive T-cell-mediated tubulitis and arteritis; and late antibody-mediated endothelial injury, which contributes to late edema, arteritis, and venulitis.

The Early Course of Kidney Allograft Rejection: Defining the Time When Rejection Begins

“…We explored the mechanisms of TCMR in a nonmechanicalsupporting mouse model, in which a host kidney remains to stabilize the host, preventing morbidity and mortality while the typical histopathologic lesions of TCMR evolve (1,2). This simulates the clinical situation in which hosts are stabilized by dialysis.…”

An Experimental Model of Acute Humoral Rejection of Renal Allografts Associated with Concomitant Cellular Rejection

“…11,13 Rejection mechanisms in murine kidney allografts have been characterized in naïve recipients in which acute cellular rejection precedes but overlaps with the slower developing AHR. 14 Pre-existing alloantibodies attributable to blood transfusion, pregnancy, or previous transplantation are present in ϳ25% of the US population. 15 These alloantibodies are a significant impediment to transplantation in many instances.…”

Banff 2003 Meeting Report: New Diagnostic Insights and Standards

“…This model shows spontaneous homeostasis in that the interstitial infiltration actually stabilizes or regresses spontaneously after day 7 even though the tubulitis progresses. The results also suggest independent homeostatic control of inflammation/IFN-c effects, invasive tubulitis, endothelialitis and antibody-mediated effects (1).…”