Reza Abdi

Publications (46)273.76 Total impact

• Article: Jagged2-Signaling Promotes IL-6-dependent Transplant Rejection.

  Leonardo V Riella, Jun Yang, Susanne Chock, Kassem Safa, Ciara N Magee, Vijay Vanguri, Wassim Elyaman, Youmna Lahoud, Hideo Yagita, Reza Abdi, Nader Najafian, José O Medina-Pestana, Anil Chandraker
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  ABSTRACT: The Notch pathway is an important intercellular signaling pathway that plays a major role in controlling cell fate. Accumulating evidence indicates that Notch and its ligands present on APCs might be important mediators of Th-cell differentiation. In this study, we investigated the role of Jagged2 in murine cardiac transplantation by using a signaling Jagged2 mAb (Jag2) that activates RBP-Jκ. While administration of Jag2 mAb had little effect on graft survival in the fully allogeneic mismatched model BALB/c→B6, it hastened rejection in CD28-deficient recipients. Similarly, Jag2 precipitated rejection in the bm12→B6 model. In this MHC class II-mismatched model, allografts spontaneously survive for >56 days due to the emergence of Treg cells that inhibit the expansion of alloreactive T cells. The accelerated rejection was associated with upregulation of Th2 cytokines and proinflammatory cytokine IL-6, despite expansion of Treg cells. Incubation of Treg cells with recombinant IL-6 abrogated their inhibitory effects in vitro. Furthermore, neutralization of IL-6 in vivo protected Jag2-treated recipients from rejection and Jagged2 signaling was unable to further accelerate rejection in the absence of Treg cells. Our findings therefore suggest that Jagged2 signaling can affect graft acceptance by upregulation of IL-6 and consequent resistance to Treg-cell suppression.
  European Journal of Immunology 03/2013; · 5.10 Impact Factor
• Article: Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7.

  Andrea Vergani, Sara Tezza, Francesca D'Addio, Carmen Fotino, Kaifeng Liu, Monika Niewczas, Roberto Bassi, R Damaris Molano, Sonja Kleffel, Alessandra Petrelli, [......], Maria Frigerio, Gary Visner, Fabio Grassi, Maria E Ferrero, Domenico Corradi, Reza Abdi, Camillo Ricordi, Mohamed H Sayegh, Antonello Pileggi, Paolo Fiorina
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  ABSTRACT: BACKGROUND: Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes as well as with the development of complications including infections and malignancies. The development of a novel, short-term and effective immunomodulatory protocol will thus be an important achievement. The purine adenosine 5'-triphosphate (ATP), released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation. METHODS AND RESULTS: We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP (oATP) promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T cell activation, Th1/Th17 differentiation and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate Th1/Th17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well. CONCLUSIONS: P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.
  Circulation 12/2012; · 14.74 Impact Factor
• Article: The novel therapeutic effect of phosphoinositide 3-kinase-γ inhibitor AS605240 in autoimmune diabetes.

  Jamil Azzi, Robert F Moore, Wassim Elyaman, Marwan Mounayar, Najib El Haddad, Sunmi Yang, Mollie Jurewicz, Ayumi Takakura, Alessandra Petrelli, Paolo Fiorina, Thomas Ruckle, Reza Abdi
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  ABSTRACT: Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes.
  Diabetes 03/2012; 61(6):1509-18. · 8.29 Impact Factor
• Source

  Available from: PubMed Central

  Article: Immunosuppressive Activity of Size-Controlled PEG-PLGA Nanoparticles Containing Encapsulated Cyclosporine A.

  Li Tang, Jamil Azzi, Mincheol Kwon, Marwan Mounayar, Rong Tong, Qian Yin, Robert Moore, Nikolaos Skartsis, Timothy M Fan, Reza Abdi, Jianjun Cheng
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  ABSTRACT: We encapsulated cyclosporine A (CsA) in poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) (PEG-PLGA) nanoparticles (NPs) by nanoprecipitation of CsA and PEG-PLGA. The resulting CsA/PEG-PLGA-NPs were <100 nm in diameter with a narrow particle size distribution. The NP size could be controlled by tuning the polymer concentration, solvent, or water/solvent ratio during formulation. The PEGylated NPs maintained non-aggregated in salt solution. Solid NPs lyoprotected with bovine serum albumin were prepared for the convenience of storage and transportation. The release kinetics of CsA (55.6% released on Day 1) showed potential for maintaining therapeutic CsA concentrations in vivo. In T-cell assays, both free CsA and CsA/PEG-PLGA-NPs suppressed T-cell proliferation and production of inflammatory cytokines dose dependently. In a mixed lymphocyte reaction assay, the IC(50) values for free CsA and CsA/PEG-PLGA-NPs were found to be 30 and 35 ng/mL, respectively. This nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and potentially reduced toxicity.
  Journal of Transplantation 01/2012; 2012:896141.
• Article: Role of nuclear factor of activated T cell (NFAT) transcription factors in skin and vascularized cardiac allograft rejection.

  Takuya Ueno, Akira Yamada, Toshiro Ito, Melissa Y Yeung, Rostic Gorbatov, Tetsunosuke Shimizu, Reza Abdi, Mohamed H Sayegh, Hugh Auchincloss, Nader Najafian
  Transplantation 09/2011; 92(5):e26-7. · 4.00 Impact Factor
• Article: The novel role of SERPINB9 in cytotoxic protection of human mesenchymal stem cells.

  Najib El Haddad, Robert Moore, Dean Heathcote, Marwan Mounayar, Jamil Azzi, Bechara Mfarrej, Ibrahim Batal, Christopher Ting, Mark Atkinson, Mohamed H Sayegh, Philip G Ashton-Rickardt, Reza Abdi
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  ABSTRACT: Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC-based therapies for diseases.
  The Journal of Immunology 09/2011; 187(5):2252-60. · 5.79 Impact Factor
• Article: Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1.

  Paolo Fiorina, Mollie Jurewicz, Andrea Vergani, Alessandra Petrelli, Michele Carvello, Francesca D'Addio, Jonathan G Godwin, Kenneth Law, Erxi Wu, Ze Tian, Gebhard Thoma, Jiri Kovarik, Stefano La Rosa, Carlo Capella, Scott Rodig, Hans-Guenter Zerwes, Mohamed H Sayegh, Reza Abdi
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  ABSTRACT: Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on hematopoietic stem cells (HSCs) and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of HSCs to the periphery. Because of their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative costimulatory molecule programmed death ligand 1 (PD-L1), and HSCs extracted from wild-type mice, but not from PD-L1 knockout mice, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 knockout mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism.
  The Journal of Immunology 01/2011; 186(1):121-31. · 5.79 Impact Factor
• Source

  Available from: Andrea Augello

  Article: Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes.

  Mollie Jurewicz, Sunmi Yang, Andrea Augello, Jonathan G Godwin, Robert F Moore, Jamil Azzi, Paolo Fiorina, Mark Atkinson, Mohamed H Sayegh, Reza Abdi
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  ABSTRACT: A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo. NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined. NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs. These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.
  Diabetes 12/2010; 59(12):3139-47. · 8.29 Impact Factor
• Article: Mesenchymal stem cells express serine protease inhibitor to evade the host immune response.

  Najib El Haddad, Dean Heathcote, Robert Moore, Sunmi Yang, Jamil Azzi, Bechara Mfarrej, Mark Atkinson, Mohamed H Sayegh, Jeng-Shin Lee, Philip G Ashton-Rickardt, Reza Abdi
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  ABSTRACT: Clinical trials using mesenchymal stem cells (MSCs) have been initiated worldwide. An improved understanding of the mechanisms by which allogeneic MSCs evade host immune responses is paramount to regulating their survival after administration. This study has focused on the novel role of serine protease inhibitor (SPI) in the escape of MSCs from host immunosurveillance through the inhibition of granzyme B (GrB). Our data indicate bone marrow-derived murine MSCs express SPI6 constitutively. MSCs from mice deficient for SPI6 (SPI6(-/-)) exhibited a 4-fold higher death rate by primed allogeneic cytotoxic T cells than did wild-type MSCs. A GrB inhibitor rescued SPI6(-/-) MSCs from cytotoxic T-cell killing. Transduction of wild-type MSCs with MigR1-SPI6 also protected MSCs from cytotoxic T cell-mediated death in vitro. In addition, SPI6(-/-) MSCs displayed a shorter lifespan than wild-type MSCs when injected into an allogeneic host. We conclude that SPI6 protects MSCs from GrB-mediated killing and plays a pivotal role in their survival in vivo. Our data could serve as a basis for future SPI-based strategies to regulate the survival and function of MSCs after administration and to enhance the efficacy of MSC-based therapy for diseases.
  Blood 11/2010; 117(4):1176-83. · 9.90 Impact Factor
• Source

  Available from: illinois.edu

  Article: Polylactide-cyclosporin A nanoparticles for targeted immunosuppression.

  Jamil Azzi, Li Tang, Robert Moore, Rong Tong, Najib El Haddad, Takurin Akiyoshi, Bechara Mfarrej, Sunmi Yang, Mollie Jurewicz, Takaharu Ichimura, Neal Lindeman, Jianjun Cheng, Reza Abdi
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  ABSTRACT: Polymeric nanoparticles (NPs), prepared via coprecipitation of drugs and polymers, are promising drug delivery vehicles for treating diseases with improved efficacy and reduced toxicity. Here, we report an unprecedented strategy for preparing polylactide-cyclosporine A (PLA-CsA) NPs (termed CsA-NPs) through CsA-initiated ring-opening polymerization of lactide (LA) followed by nanoprecipitation. The resulting CsA-NPs have sub-100 nm sizes and narrow particle size distributions, and release CsA in a sustained manner without a "burst"-release effect. Both free CsA and CsA-NPs displayed comparable suppression of T-cell proliferation and production of inflammatory cytokines in various T-cell assays in a dose-dependent manner. The IC(50) values for CsA and CsA-NPs were 27.5 and 72.0 ng/ml, respectively. As lymph nodes are the main loci for T-cell activation, we coupled dendritic cells (DCs) with CsA-NPs and successfully delivered CsA selectively to the lymph nodes. Our studies indicated that CsA-NPs could be internalized in the DCs with a sustained release of CsA to the culture medium, suppressing alloreactive T-cell proliferation. Allogeneic DCs loaded with CsA-NPs were able to migrate to the draining lymph nodes where the T-cell priming was significantly reduced without any systemic release. This innovative nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and reduced toxicity.
  The FASEB Journal 10/2010; 24(10):3927-38. · 5.71 Impact Factor
• Source

  Available from: Andrea Vergani

  Article: A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice.

  Andrea Vergani, Francesca D'Addio, Mollie Jurewicz, Alessandra Petrelli, Toshihiko Watanabe, Kaifeng Liu, Kenneth Law, Christian Schuetz, Michele Carvello, Elena Orsenigo, Shaoping Deng, Scott J Rodig, Javeed M Ansari, Carlo Staudacher, Reza Abdi, John Williams, James Markmann, Mark Atkinson, Mohamed H Sayegh, Paolo Fiorina
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  ABSTRACT: To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal. Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice). The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.
  Diabetes 09/2010; 59(9):2253-64. · 8.29 Impact Factor
• Article: The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing.

  Paolo Fiorina, Giorgio Pietramaggiori, Saja S Scherer, Mollie Jurewicz, Jasmine C Mathews, Andrea Vergani, Gebhard Thomas, Elena Orsenigo, Carlo Staudacher, Stefano La Rosa, Carlo Capella, Adelaide Carothers, Hans-Gunter Zerwes, Livio Luzi, Reza Abdi, Dennis P Orgill
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  ABSTRACT: Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin(-)c-Kit(+)Sca-1(+)) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34(+)VEGFR(+)) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4-CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1α in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BM-PCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1α and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferation.
  Cell Transplantation 08/2010; 19(11):1369-81. · 5.13 Impact Factor
• Article: Gene polymorphisms in renal transplantation.

  Monica Grafals, Leila Kamal, Daniel Chung, Reza Abdi
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  ABSTRACT: A vast majority of gene polymorphism studies in renal transplantation focus on short-term outcomes such as acute rejection. The main purpose of this article is to review the literature available and studies that have examined the association between the gene polymorphisms and long-term renal allograft functions. In this review, we focus on commonly reported genes in the renin angiotensin system, transforming growth factor-beta gene, and metalloproteinases on the incidence and progression of chronic renal allograft dysfunction.
  Seminars in Nephrology 07/2010; 30(4):418-25. · 2.12 Impact Factor
• Article: Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

  Steven Gabardi, Sushrut S Waikar, Spencer Martin, Keri Roberts, Jie Chen, Lea Borgi, Hussein Sheashaa, Christine Dyer, Sayeed K Malek, Stefan G Tullius, Nidyanandh Vadivel, Monica Grafals, Reza Abdi, Nader Najafian, Edgar Milford, Anil Chandraker
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  ABSTRACT: Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.
  Clinical Journal of the American Society of Nephrology 07/2010; 5(7):1298-304. · 5.23 Impact Factor
• Article: Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation.

  David H McDermott, Susan E Conway, Tao Wang, Stacy M Ricklefs, Manza A Agovi, Stephen F Porcella, Huong Thi Bich Tran, Edgar Milford, Stephen Spellman, Reza Abdi
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  ABSTRACT: Despite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen-matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P = .005) and overall survival (P = .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P = .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy.
  Blood 03/2010; 115(11):2311-8. · 9.90 Impact Factor
• Article: Ischemic injury enhances dendritic cell immunogenicity via TLR4 and NF-kappa B activation.

  Mollie Jurewicz, Ayumi Takakura, Andrea Augello, Said Movahedi Naini, Takaharu Ichimura, Kambiz Zandi-Nejad, Reza Abdi
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  ABSTRACT: Ischemic (isc) injury during the course of transplantation enhances the immunogenicity of allografts and thus results in poorer graft outcome. Given the central role of dendritic cells (DCs) in mounting alloimmune responses, activation of donor DCs by ischemia may have a primary function in the increased immunogenicity of isc allografts. In this study, we sought to investigate the effect of ischemia on DC activity in vitro. Following induction of ischemia, bone marrow-derived DCs were shown to augment allogeneic T cell proliferation as well as the IFN-gamma response. Isc DCs produced greater levels of IL-6, and isc insult was concurrent with NF-kappaB activation. TLR4 ligation was also shown to occur in isc DCs, most likely in response to the endogenous ligand heat shock protein 70, which was found to be elevated in DCs following isc injury, and lack of TLR4 abrogated the observed effects of isc DCs. As compared with control DCs, isc DCs injected into the footpads of mice demonstrated enhanced migration, which was concomitant with increased recipient T cell activity. Moreover, isc DCs underwent a greater degree of apoptosis in the lymph nodes of injected mice, which may further demonstrate enhanced immunogenicity of isc DCs. We thus show that isc injury of DCs enhances DC function, augments the allogeneic T cell response, and occurs via ligation of TLR4, followed by activation of NF-kappaB. These data may serve to identify novel therapeutic targets to attenuate graft immunogenicity following ischemia.
  The Journal of Immunology 02/2010; 184(6):2939-48. · 5.79 Impact Factor
• Article: Immunological aspects of pancreatic islet cell transplantation.

  Jamil Azzi, Abdallah S Geara, Suzanne El-Sayegh, Reza Abdi
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  ABSTRACT: Type 1 diabetes mellitus (T1DM) is one of the most common diseases of childhood. Insulin discovery changed the clinical course of T1DM from an acutely fatal disease to a chronic disease, but this discovery was later found to be inefficient to control its long-term complications. Whole-pancreas and islet cell transplantation seem to provide a potential solution by restoring the normal physiology of glucose-insulin homeostasis. Although islet transplantation is less invasive than whole-pancreas transplantation, the insulin-free state after islet transplantation remained low (10%) at 5 years after surgery. Here, we will present the specific immunologic challenges that are specific to islet cell transplantation, including instant blood-mediated inflammatory reaction and the recurrence of autoimmunity. We will also briefly discuss the immunosuppressive regimens used and the recent radiologic techniques in the detection of engraftment and early rejection of islet cells.
  Expert Review of Clinical Immunology 01/2010; 6(1):111-24. · 2.07 Impact Factor
• Article: Immunoregulatory gene polymorphisms and graft-versus-host disease.

  Susan E Conway, Reza Abdi
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  ABSTRACT: Graft-versus-host disease (GVHD) remains a significant complication that greatly enhances morbidity and mortality associated with hematopoietic stem cell transplantation. Key immunoregulatory molecules have been implicated in the pathogenesis of GVHD, but the mechanisms by which these molecules affect the incidence and severity of GVHD have not been fully elucidated. The effects of genetic polymorphisms in immunoregulatory molecules, including cytokines, costimulatory and adhesion molecules, pharmacogenes and growth factors, have been shown to play a central role in GVHD. The results of these polymorphism studies contribute to the identification of predictive risk factors for GVHD based on individual polymorphism makeup. This review summarizes investigations of genetic polymorphisms in immunoregulatory molecules significantly associated with GVHD over the last 5 years.
  Expert Review of Clinical Immunology 09/2009; 5(5):523-34. · 2.07 Impact Factor
• Article: The renin-angiotensin system: an old, newly discovered player in immunoregulation.

  Abdallah S Geara, Jamil Azzi, Mollie Jurewicz, Reza Abdi
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  ABSTRACT: Clinical and experimental studies that discuss the different immune functions of the renin-angiotensin system (RAS) in kidney diseases were reviewed, with emphasis on studies of kidney transplantation. The RAS has been shown to affect both the innate and adaptive immune responses and has a well-established role in fibrinogenesis. Of special clinical interest is the ability of the RAS to activate the transforming growth factor beta(1) and the Smad pathways leading to fibrinogenesis. In addition to the RAS enhancing effect on the activity of T cells, several components of the RAS have also been shown to be chemotactic to macrophages, T cells, and natural killer cells. Experimental studies have found that RAS blockade decreases the histologic lesions of chronic allograft nephropathy but can enhance acute graft vasculopathy. Although the blockade of RAS has been commonly practiced to reduce posttransplantation hypertension, proteinuria, and erythrocytosis, however, its role in prolonging graft survival is not well established.
  Transplantation reviews (Orlando, Fla.) 08/2009; 23(3):151-8.
• Source

  Available from: Andrea Augello

  Article: Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes.

  Paolo Fiorina, Mollie Jurewicz, Andrea Augello, Andrea Vergani, Shirine Dada, Stefano La Rosa, Martin Selig, Jonathan Godwin, Kenneth Law, Claudia Placidi, R Neal Smith, Carlo Capella, Scott Rodig, Chaker N Adra, Mark Atkinson, Mohamed H Sayegh, Reza Abdi
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  ABSTRACT: Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
  The Journal of Immunology 07/2009; 183(2):993-1004. · 5.79 Impact Factor