Monday, September 27, 2010 2:00 PM - American Society for ...

immunosuppression (IS) for 3 months is converted to sirolimus (SRL) and MMF followed by ISwithdrawal, first MMF and then SRL at 12-30 months post-op. Serial PBMC flow immunophenotyping(IP) and sequential Treg-MLR inhibition/recruitment assays are performed. In the Treg-MLR,cryopreserved recipient pre-RT PBMC (CFSE labeled) respond to irradiated donor or third partystimulating PBMC in the presence of (cryopreserved) pre- vs post- RT recipient PBMC as modulators.Then, lymphoproliferation and newly generated (recruited) CD4 + CD25 high FOXP3 + responding cells aremeasured by flow.Results: The first 4 patients are now between 18 and 30 months post-op with IS (SRL monotherapy)dosing ranging from none to 1 mg QOD with no rejection (clean 1 & 2 year biopsies and no cell growth inbiopsy cultures). Immunophenotyping of PBMC indicated that the (CD127 - ) CD4 + CD25 high FOXP3 +(natural) Tregs increased >3X in recipient PBMC up to 30 months post-RT. In the Treg-MLR, recipientPBMC from 1 year post-RT inhibited anti-donor cell proliferation and increased the proportion(recruitment) of newly developed donor-specific recipient responder CD4 + CD25 high FOXp3 + cells by 10-fold (n=4). Chimerism transiently reached 3% in some recipients at 3 to 6 months (real-time quantitativePCR assay).Conclusions: DHSC in AL treated HLA-identical RT recipients converted from TAC & MMF to SRL andthen IS withdrawn, is associated with high PBMC Tregs, and in the Treg-MLR with donor-specificinhibition and Treg recruitment.23-ORKIR3DS1-2DS1-2DS5, RECEPTORS IMPLICATED IN NK CELL ACTIVATION PROVIDE ARISK OF DEVELOPING ADVANCED STAGE BREAST CANCER.Elham Ashouri 1 , Abbas Ghaderi 1 , Raja Rajalingam 2 . 1 Shiraz Institute for Cancer Research, ShirazUniversity of Medical Sciences, Shiraz, Islamic Republic of Iran; 2 UCLA Immunogenetics Center,Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Universityof California at Los Angeles, Los Angeles, CA, USA.Aim: Polymorphic KIRs are the key receptors of human NK cells that trigger early immune responseagainst infection and tumors. Here we investigated if certain KIR genes are associated with breast cancer.Methods: DNA from 167 women with breast cancer diagnosed at the multidisciplinary breast cancer unitof Shiraz Institute for Cancer Research, Iran, and 278 healthy controls from the same geographical areawere typed for 16 KIR genes using a duplex-PCR typing system.Results: The frequency of Bx genotypes that possess 2-6 activating KIR genes were predominant in thepatients compared to the controls (84.4% vs. 72.6%, P = 0.005; 95% CI, 1.24-3.34, OR = 2.04). ActivatingKIR genes, 3DS1 (46.7% vs. 34.1%, P = 0.009; 95% CI, 1.14-2.5, OR = 1.68), 2DS1 (55.6% vs. 36.3%, P= 0.00007; 95% CI, 1.48-3.25, OR = 2.2) and 2DS5 (42.5% vs. 25.5%, P = 0.0002; 95% CI, 1.43-3.24, OR= 2.15) were significantly increased in breast cancer compared to the controls. Particularly, 36.4% of thepatients carried all these three activating KIR genes compared to only 21.4% controls (P = 0.00067; 95%CI, 1.37-3.2, OR = 2.09). Notably, 41.8% of the patients with advanced stage III cancer carried all thesethree KIRs.Conclusions: These findings contrast the classical view that activating NK cell receptors mediatespontaneous lysis of tumor transformed cells. NK cells expressing 3DS1-2DS1-2DS5 may trigger alocalized hyperresponsiveness exacerbating cancer growth. Consistent with this findings, a detrimental rolefor NK cells against cancer and non-viral pathogens has been suggested from the following studies:increased 3DS1 in patients with cervical neoplasia (J Exp Med 2005, 201:1069), depletion of NK cellsincreased the ability of the host to control L.Monocytogenes (J Immunol 1994, 152:1873); host NK cells arenecessary for the growth of human filarial parasite B.Malayi (J Immunol 1998, 161:1428).24-OREFFECT OF KILLER CELL IMMUNOGLOBULIN LIKE RECEPTOR (KIR) AND HUMANLEUKOCYTE ANTIGEN (HLA) LIGAND INCOMPATIBILITY ON HUMAN RENALTRANSPLANTATION: ASSOCIATION WITH ARTERIAL THICKENING AND TUBULITIS.Faisal M. Khan 1,2 , Jagdeep Doulla 2 , Meena Assad 2 , Aylin Sar 2 , Ipek I. Gonul 2 , Serdar Yilmaz 2 , NoureddineBerka 1,2 . 1 Calgary Laboratory Services, Calgary, AB, Canada; 2 University of Calgary, Calgary, AB,Canada.