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Jun Zou, Brian Duffy, Michael Slade, Andrew Lee Young, Nancy Steward, Ramsey Hachem, T Mohanakumar
Fiberoptic bronchoscopy and transbronchial lung biopsy are currently the gold standard for detection of acute rejection following human lung transplantation (LTx). However, these surveillance procedures are expensive and invasive. Up to now, there are few new methods that have demonstrated clinical utility for detecting early stages of rejection following human lung transplantation. We optimized and technically validated a novel method to quantify donor-derived circulating cell free DNA (DcfDNA) that can be used as an early biomarker for lung allograft rejection...
April 2017: Human Immunology
J Zou, R Romee, M Slade, D Phelan, J Keller, T Mohanakumar, B J Grossman
No abstract text is available yet for this article.
February 20, 2017: Bone Marrow Transplantation
Ankit Bharat, T Mohanakumar
Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs...
2017: Journal of Immunology Research
Zhongping Xu, Wei Yang, Nancy Steward, Stuart C Sweet, Lara Danziger-Isakov, Peter S Heeger, T Mohanakumar
BACKGROUND: Acute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS), remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR). METHODS: We determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months following LTx...
December 8, 2016: Transplantation
T Sengupta, J Vinayagam, R Singh, P Jaisankar, K P Mohanakumar
Plant-derived natural products have made their own niche in the treatment of neurological diseases since time immemorial. Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, has no cure and the treatment available currently is symptomatic. This chapter thoughtfully and objectively assesses the scientific basis that supports the increasing use of these plant-derived natural products for the treatment of this chronic and progressive disorder. Proper considerations are made on the chemical nature, sources, preclinical tests and their validity, and mechanisms of behavioural or biochemical recovery observed following treatment with various plants derived natural products relevant to PD therapy...
2016: Advances in Neurobiology
Ramiro Fernandez, Stephen Chiu, Kirtee Raparia, Puneet Garcha, Carol Farver, Marie Budev, Anat R Tambur, Malcolm M DeCamp, Scott Budinger, Harris Perlman, T Mohanakumar, Ankit Bharat
A third of lung recipients have preexisting antibodies against nonhuman leukocyte self-antigens (nHAbs) present in the lung tissue. These nHAbs also form de novo in about 70% of patients within 3 years after transplantation. Both preexisting and de novo nHAbs can cause murine lung allograft dysfunction. However, their role in human transplantation remains unclear. We report hyperacute rejection after right lung transplant in a recipient with preexisting nHAbs. The recipient of the left lung from the same donor had an uneventful initial course, but de novo nHAbs developed at 3 weeks, leading to acute humoral rejection...
October 2016: Annals of Thoracic Surgery
Zhenyu Xiao, Babak Banan, Min Xu, Jianluo Jia, Pamela T Manning, Ronald R Hiebsch, Muthukumar Gunasekaran, Gundumi A Upadhya, William A Frazier, Thalachallour Mohanakumar, Yiing Lin, William C Chapman
BACKGROUND: Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling...
July 2016: Transplantation
M Gunasekaran, Z Xu, D K Nayak, M Sharma, R Hachem, R Walia, R M Bremner, M A Smith, T Mohanakumar
The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of HLA, lung-associated self-antigens (SAgs) and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxRs) who were stable or who had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and western blotting for annexin V SAgs, collagen V (Col-V) and Kα1 tubulin were examined by electron microscopy; miRNAs were profiled by a miRNA array...
February 2017: American Journal of Transplantation
A J Demetris, C Bellamy, S G Hübscher, J O'Leary, P S Randhawa, S Feng, D Neil, R B Colvin, G McCaughan, J J Fung, A Del Bello, F P Reinholt, H Haga, O Adeyi, A J Czaja, T Schiano, M I Fiel, M L Smith, M Sebagh, R Y Tanigawa, F Yilmaz, G Alexander, L Baiocchi, M Balasubramanian, I Batal, A K Bhan, J Bucuvalas, C T S Cerski, F Charlotte, M E de Vera, M ElMonayeri, P Fontes, E E Furth, A S H Gouw, S Hafezi-Bakhtiari, J Hart, E Honsova, W Ismail, T Itoh, N C Jhala, U Khettry, G B Klintmalm, S Knechtle, T Koshiba, T Kozlowski, C R Lassman, J Lerut, J Levitsky, L Licini, R Liotta, G Mazariegos, M I Minervini, J Misdraji, T Mohanakumar, J Mölne, I Nasser, J Neuberger, M O'Neil, O Pappo, L Petrovic, P Ruiz, Ö Sağol, A Sanchez Fueyo, E Sasatomi, A Shaked, M Shiller, T Shimizu, B Sis, A Sonzogni, H L Stevenson, S N Thung, G Tisone, A C Tsamandas, A Wernerson, T Wu, A Zeevi, Y Zen
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations...
June 7, 2016: American Journal of Transplantation
Stephen Chiu, Ramiro Fernandez, Vijay Subramanian, Haiying Sun, Malcolm M DeCamp, Daniel Kreisel, Harris Perlman, G R Scott Budinger, Thalachallour Mohanakumar, Ankit Bharat
More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ankit Bharat, Stephen Chiu, Zhikun Zheng, Haiying Sun, Anjana Yeldandi, Malcolm M DeCamp, Harris Perlman, G R Scott Budinger, Thalachallour Mohanakumar
Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-α1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preexisting lung-restricted antibodies can mediate PGD and prevent allotolerance. A murine syngeneic (C57BL/6) or allogeneic (C57BL/6 to BALB/c) left lung transplantation model was used. Rabbit polyclonal antibodies were produced against KAT and Col-V and injected pretransplantation...
October 2016: American Journal of Respiratory Cell and Molecular Biology
D K Nayak, F Zhou, M Xu, J Huang, M Tsuji, R Hachem, T Mohanakumar
Steady-state alveolar macrophages (AMs) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AMs of recipient origin seed the transplanted lungs. Origin of AMs was accessed using donor-recipient HLA mismatches...
August 2016: American Journal of Transplantation
William H Hoffman, Monal Sharma, Daniela Cihakova, Monica V Talor, Noel R Rose, T Mohanakumar, Gregory G Passmore
Diabetic cardiomyopathy (DC) is an independent phenotype of diabetic cardiovascular disease. The understanding of the pathogenesis of DC in young patients with type 1 diabetes (T1D) is limited. The cardiac insults of diabetic ketoacidosis (DKA) and progression of DC could include development of antibodies (Abs) to cardiac self-antigens (SAgs) such as: myosin (M), vimentin (V) and k-alpha 1 tubulin (Kα1T). The goal of this study is to determine if the insults of severe DKA and its inflammatory cascade are associated with immune responses to SAgs...
2016: Autoimmunity
Z Xu, S Ramachandran, M Gunasekaran, D Nayak, N Benshoff, R Hachem, A Gelman, T Mohanakumar
Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2K(b) was administered intrabronchially into Batf (-/-) and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf (-/-) mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction...
April 2016: American Journal of Transplantation
Chang Liu, Brian Duffy, Jeffrey J Bednarski, Cecelia Calhoun, Lindsay Lay, Barrett Rundblad, Jacqueline E Payton, Thalachallour Mohanakumar
OBJECTIVES: To report the laboratory investigation of a case of severe combined immunodeficiency (SCID) with maternal T-cell engraftment, focusing on the interference of human leukocyte antigen (HLA) typing by blood chimerism. METHODS: HLA typing was performed with three different methods, including sequence-specific primer (SSP), sequence-specific oligonucleotide, and Sanger sequencing on peripheral blood leukocytes and buccal cells, from a 3-month-old boy and peripheral blood leukocytes from his parents...
February 2016: American Journal of Clinical Pathology
Vijay Subramanian, Muthukumar Gunasekaran, Joseph P Gaut, Donna Phelan, Neeta Vachharajani, Rowena Delos Santos, Jason Wellen, Surendra Shenoy, T Mohanakumar
Immune responses to HLA and tissue-restricted self-antigens (SAgs) have been proposed to play a role in the pathogenesis of renal allograft (KTx) rejection. However, ABO incompatible (ABOi) KTx recipients (KTxR) following depletion of antibodies (Abs) to blood group antigens had fewer rejections. To determine the mechanisms, pre- and post-transplant sera from ABOi (n=18) and ABO-compatible (ABOc) (n=45) KTxR were analyzed for Abs against HLA class I and II by LABScreen single antigen assay. The development of Abs to SAgs was measured by ELISA...
January 2016: Human Immunology
Zhenyu Xiao, Haniee Chung, Babak Banan, Pamela T Manning, Katherine C Ott, Shin Lin, Benjamin J Capoccia, Vijay Subramanian, Ronald R Hiebsch, Gundumi A Upadhya, Thalachallour Mohanakumar, William A Frazier, Yiing Lin, William C Chapman
Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over-expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPα...
May 1, 2015: Cancer Letters
Z Xu, D Nayak, W Yang, G Baskaran, S Ramachandran, N Sarma, A Aloush, E Trulock, R Hachem, G A Patterson, T Mohanakumar
The pathogenesis of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation (LT) is poorly understood. We hypothesized that development of antibodies to HLA (DSA) is associated with dysregulation of microRNA (miRNA) that predisposes BOS. Towards this, miRNA profiling of mononuclear cells from 10 stable LT (DSA(-) BOS(-) ), 10 LT with DSA(+) BOS(-) (DSA group) and 10 LT with DSA(+) BOS(+) (BOS group) were performed. Prediction by mirPath indicated that differential miRNAs in DSA(+) BOS(-) compared to stable are significantly up-regulated (relative fold >2, p < 0...
July 2015: American Journal of Transplantation
Bernard J DuBray, Kendra D Conzen, Gundumi A Upadhya, Kristen L Gunter, Jianluo Jia, Brett L Knolhoff, Thallachallour Mohanakumar, William C Chapman, Christopher D Anderson
BACKGROUND: Ischemia-reperfusion injury (IRI) to the liver continues to be a source of significant morbidity, especially in patients with hepatic steatosis. This is a growing problem given the increase in nonalcoholic fatty liver disease. B-cell lymphoma-2 homology3-only members of the B-cell lymphoma-2 protein family are known mediators of cellular apoptosis, although their role in hepatic IRI is still emerging. The goal of this study was to investigate the effect of Bim and Bid on warm hepatic IRI in the setting of steatosis...
April 2015: Journal of Surgical Research
Zhen-Yu Xiao, Babak Banan, Jianluo Jia, Pamela T Manning, Ronald R Hiebsch, Muthukumar Gunasekaran, Gundumi A Upadhya, William A Frazier, Thalachallour Mohanakumar, Yiing Lin, William C Chapman
Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant...
April 2015: Liver Transplantation
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