Person:
McGrath, Martina

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

McGrath

First Name

Martina

Name

McGrath, Martina

Filters

2012 - 20186

Settings

Author's Publications: search.filters.isAuthorOfPublication.c25844ef-7678-4901-b094-250b37ca82a6

Search Results

Now showing 1 - 6 of 6
  • Thumbnail Image
    Publication
    Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity
    (Nature Publishing Group UK, 2018) Uehara, Mayuko; Solhjou, Zhabiz; Banouni, Naima; Kasinath, Vivek; Xiaqun, Ye; Dai, Li; Yilmam, Osman; Yilmaz, Mine; Ichimura, Takaharu; Fiorina, Paolo; Martins, Paulo N.; Ohori, Shunsuke; Guleria, Indira; Maarouf, Omar H.; Tullius, Stefan; McGrath, Martina; Abdi, Reza
    Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.
  • Thumbnail Image
    Publication
    Regulation of T cell alloimmunity by PI3Kγ and PI3Kδ
    (Nature Publishing Group UK, 2017) Uehara, Mayuko; McGrath, Martina; Ohori, Shunsuke; Solhjou, Zhabiz; Banouni, Naima; Routray, Sujit; Evans, Catherine; DiNitto, Jonathan P.; ElKhal, Abdallah; Turka, Laurence; Strom, Terry B.; Tullius, Stefan; Winkler, David G.; Azzi, Jamil; Abdi, Reza
    Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ −/− and PI3Kδ D910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ −/−, but not PI3Κδ D910A/D910A, recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ D910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation.
  • Thumbnail Image
    Publication
    Live Images of Donor Dendritic Cells Trafficking via CX3CR1 Pathway
    (Frontiers Media S.A., 2016) Ueno, Takuya; Kim, Pilhan; McGrath, Martina; Yeung, Melissa; Shimizu, Tetsunosuke; Jung, Keehoon; Sayegh, Mohamed; Chandraker, Anil; Abdi, Reza; Yun, Seok H.
    Background: A number of studies have demonstrated the role of CX3CR1 in regulating the migration of monocytes into peripheral tissue and their transformation into dendritic cell (DC). No data are yet available on the importance of chemokine pathways in regulating homeostasis of DC in heart transplants. Recently, we showed that recipients of heart allografts from CX3CR1−/− donors show longer survival. To assess the trafficking of dDC, we have developed and tested a novel in vivo imaging tool in CX3CR1GFP/+ DC (B6 background) heart graft into BALB/c recipient model. Results: Majority of GFP+ cells were noted in the middle of cardiac myocyte. However few hours post transplant, they experienced morphological changes including stretching their extensions (3 and 24 h). However, images from 72 h at cardiac graft showed many of GFP+ cells moved to vessel areas. GFP+ cells were detected in near vessel wall. Only one GFP+ cell was observed in three lymph nodes (two mesenteric and one inguinal) (72 h). Conclusion: Our data indicate that immediately post transplant dDC undergo morphological changes and traffic out of the organs via systemic circulation. While, we still noted presence of dDC in the transplanted organs, their trafficking to lymphoid tissue remains to be fully explored.
  • Thumbnail Image
    Publication
    Targeted Delivery of Immunomodulators to Lymph Nodes
    (2016) Azzi, Jamil; Yin, Qian; Uehara, Mayuko; Ohori, Shunsuke; Tang, Li; Cai, Kaimin; Ichimura, Takaharu; McGrath, Martina; Maarouf, Omar; Kefaloyianni, Eirini; Loughhead, Scott; Petr, Jarolim; Sun, Qidi; Kwon, Mincheol; Tullius, Stefan; von Andrian-Werburg, Ulrich; Cheng, Jianjun; Abdi, Reza
    SUMMARY Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node address in molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.
  • Thumbnail Image
    Publication
    The Limits of Linked Suppression for Regulatory T Cells
    (Frontiers Media S.A., 2016) Ito, Toshiro; Yamada, Akira; Batal, Ibrahim; Yeung, Melissa; McGrath, Martina; Sayegh, Mohamed; Chandraker, Anil; Ueno, Takuya
    Background: We have previously found that CD4+CD25+ regulatory T cells (Tregs) can adoptively transfer tolerance after its induction with costimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: (1) the Tregs that transfer tolerance have the capacity for linked suppression, (2) the determinants that stimulate the Tregs are expressed by the indirect pathway, and (3) the donor peptides contributing to these indirect determinants are derived from donor major histocompatibility complex (MHC) antigens (Ags). Methods: First heart transplants were performed from the indicated donor strain to B10.D2 recipients along with costimulatory blockade treatment (250 μg i.p. injection of MR1 on day 0 and 250 μg i.p. injection of CTLA-4 Ig on day 2). At least 8 weeks later, a second heart transplant was performed to a new B10.D2 recipient who had been irradiated with 450 cGy. This recipient was given 40 × 106 naive B10.D2 spleen cells + 40 × 106 B10.D2 spleen cells from the first (tolerant) recipient. We performed three different types of heart transplants using various donors. Results: (1) Tregs suppress the graft rejection in an Ag-specific manner. (2) Tregs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion: The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC Ags.
  • Thumbnail Image
    Publication
    The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance
    (Frontiers Research Foundation, 2012) McGrath, Martina; Najafian, Nader
    Negative costimulatory molecules, acting through so-called inhibitory pathways, play a crucial role in the control of T cell responses. This negative “second signal” opposes T cell receptor activation and leads to downregulation of T cell proliferation and promotes antigen specific tolerance. Much interest has focused upon these pathways in recent years as a method to control detrimental alloresponses and promote allograft tolerance. However, recent experimental data highlights the complexity of negative costimulatory pathways in alloimmunity. Varying effects are observed from molecules expressed on donor and recipient tissues and also depending upon the activation status of immune cells involved. There appears to be significant overlap and redundancy within these systems, rendering this a challenging area to understand and exploit therapeutically. In this article, we will review the literature at the current time regarding the major negative costimulation pathways including CTLA-4:B7, PD-1:PD-L1/PD-L2 and PD-L1:B7-1, B7-H3, B7-H4, HVEM:BTLA/CD160, and TIM-3:Galectin-9. We aim to outline the role of these pathways in alloimmunity and discuss their potential applications for tolerance induction in transplantation.