*Purpose: Prolonged cold ischemia storage (CIS) of donor transplants is a major risk factor for acute and chronic graft tissue injury.The goal of this study was to test how increased CIS time influences alloimmunity using a mouse model of renal transplantation.

*Methods: B6 (H-2^b) mice received BALB/c (H-2^d) renal allografts subjected to 0.5 h or 6 h CIS in University of Wisconsin solution (0.5 h CIS and 6 h CIS groups).

*Results: At d.14 posttransplant, recipients from 6 h CIS group had increased titers of donor-MHC class II but not class I reactive IgG alloantibodies, higher frequencies of donor-reactive IFNγ secreting T cells and significantly higher proportion of glomeruli infiltrated with macrophages compared to 0.5 h CIS controls. By d.60 posttransplant, 6 h CIS but not 0.5h CIS allografts developed extensive glomerular injury including thickened capillary loops, segmental or global sclerosis and thrombotic microangiopathy with red cell congestion, intracapillary fibrin thrombi, and mesangiolysis. B cell depletion with anti-mouse CD20 mAb inhibited DSA generation, intragraft C4d deposition and macrophage glomerular infiltration on d.14 posttransplant. These data strongly suggest that the initial glomerular injury following prolonged CIS is alloantibody-mediated. Treatment of 6 h CIS recipients with sphingosine-1-phosphate receptor 1 agonist (FTY720) reduced number of circulating T and B lymphocytes and inhibited the development of anti-MHC class II reactive DSA. Despite the presence of anti MHC class I DSA recipients treated with FTY720 had minimal vascular C4d deposition and reduced macrophage infiltration in glomeruli on day +14. Adoptive transfer of anti-donor MHC class II containing sera or monoclonal antibody into FTY720 treated recipients partially restored macrophage glomerular infiltrate

*Conclusions: These results indicate that posttransplant inflammation not only facilitates DSA development but also spreads the specificity of DSA from donor class I to class II and may thus influence renal allograft pathology. This is first demonstartion for the pathogenic role of MHC class II reactive DSA in transplant glomerulopathy.

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