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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Development of Technologies and Evaluation of Methods Used to Test the Safety of Tissue Intended for Transplantation

Principal Investigator: Shyh-Ching Lo, MD, PhD
Office / Division / Lab: OCTGT / DCGT / TVBB


General Overview

Tissue banks distribute about 1.5 million donated bone and tissue grafts to recipients each year, according to the American Association of Tissue Banks (AATB), which accredits these facilities On rare occasions allograft tissues (tissues obtained from donors) have transmitted infections to recipients. In most instances the infection was present in the donor at the time of death but was not detected. In some other cases contamination occurred during recovery, transport, processing, or storage of the tissues. Many of these instances have been investigated carefully and resulted in improved methods for screening and testing donors for infections, for preventing contamination, and for removing or inactivating organisms that may be present in allografts. The FDA's donor eligibility rule requires up-to-date and appropriate donor screening and testing and the agency's Current Good Tissue Practices rule requires methods be put in place to reduce risks during tissue processing.

Although transmission of infections is rare, a single human donor has the potential to provide tissue for over 100 transplants, which means that infected tissue from a donor has the potential to cause life-threatening infections or illnesses in over 100 recipients. Patients whose immune systems are already weakened due to disease or medical treatments are particularly vulnerable to infections transmitted by infected donated tissue.

The potential for such widespread effects of contaminated tissues makes it important for FDA to develop and evaluate industry standards for methods designed to ensure tissue sterility and disinfection and to approve tests for emerging infectious diseases that threaten the safety of donated tissues.

FDA regulates transplanted tissues, which usually come from cadaveric donors (e.g., deceased individuals) and include bone, skin, corneas, ligaments, tendons, dura mater (membrane covering the brain), and heart valves. Other regulated tissues obtained from living donors include hematopoietic stem/progenitor cells (cells that give rise to specific types of blood cells) derived from peripheral (vein) and umbilical cord blood, and reproductive tissues such as oocytes (immature eggs) and semen.

FDA began regulating the tissue industry in 1993 in order to ensure the safety and effectiveness of cellular and tissue-based products that are also drugs, biological products, or devices. More recently, the agency enhanced its ability to regulate tissues based on sound science by establishing a tissue microbiology research laboratory to study, evaluate and regulate human tissues and tissue-based products for potential risks of transmitting various infectious agents. This new laboratory is developing new methods and technologies for rapid detection and characterization of emerging infectious pathogens that threaten the safety of tissue and tissue-based products.


Scientific Overview

More than 1 million tissues are distributed as grafts for transplantation every year in the US. On rare occasions allograft tissues have transmitted infections to recipients. In most instances the infection was present in the donor at the time of death but was not detected. In some other cases, tissues were contaminated during recovery, transport, processing, or storage. Many of these instances have been investigated carefully and resulted in improved methods for screening and testing donors for infections, for preventing contamination, and for removing or inactivating organisms that may be present in allografts. The donor eligibility rule requires up-to-date and appropriate donor screening and testing. The Current Good Tissue Practices rule requires methods be put in place to reduce risks during tissue processing.

The Office of Cellular, Tissue and Gene Therapies (OCTGT) within CBER regulates human cells, tissues, and cellular and tissue-based products (HCT/Ps) in order to prevent the introduction, transmission, or spread of communicable diseases. The OCTGT is establishing a more robust regulatory scientific infrastructure and better outreach to improve regulatory practices and review performance. The tissue microbiology laboratory has recently been established under the Division of Cellular and gene therapies (DCGT) and the Division of Human Tissues (DHT) to enhance the safety and the availability of human tissues intended for transplantation. The laboratory will develop various capabilities for detecting and characterizing infectious pathogens that could threaten the safety of human tissues to be transplanted as grafts. In addition, the laboratory will assist in validating tests for determining tissue donor eligibility using cadaveric samples and actively participate in the risk assessment of relevant communicable disease agents and diseases (RCDADs).

The new methods and new technologies the laboratory is developing include:

(1) Real-time qPCR: The primer sets for PCR-detection of target microbial species considered highly pathogenic for tissue grafts are designed using algorithms that recognize different patterns of DNA sequences among different genera and species of bacteria. The primer sets proven to be highly sensitive and species or genus-specific will then be used to design the real-time qPCR array for target "high-risk" bacteria.

(2) Genomic sequencing capability using the GS FLX platform (454 Life Science) of ultra-deep, non-biased sequencing technology to examine tissue or tissue-based products for the potential hidden microbes. The newly available technology will be uniquely powerful in the detection and characterization of those previously unknown or difficult-to-culture microbes, as well as those microbial agents that transmit an infectious disease after a long incubation time.

(3) Identification of biomarkers associated with the basic mechanisms of injuries in cell/tissue exposed to various chemicals using global gene expression profiling approach. The crucial markers will then be used to develop an array to assess the degree of injury in cells and tissues exposed to various chemicals or disinfectants used in tissue processing.


Publications

Exp Biol Med 2012 Dec 1;237(12):1413-23
Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells.
Li T, Zhao H, Hung GC, Han J, Tsai S, Li B, Zhang J, Puri RK, Lo SC

MBio 2012 Sep 18;3(5):1-7
A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus.
Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI

J Clin Microbiol 2012 Aug;50(8):2770-3
Identification of DNA signatures suitable for use in development of real-time PCR assays by whole-genome sequence approaches: use of Streptococcus pyogenes in a pilot study.
Hung GC, Nagamine K, Li B, Lo SC

PLoS One 2012;7(8):e43246
Development of real-time PCR array for simultaneous detection of eight human blood-borne viral pathogens.
Pripuzova N, Wang R, Tsai S, Li B, Hung GC, Ptak RG, Lo SC

Science 2011 Nov 11;334(6057):814-7
Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study.
Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J Jr, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP, Blood XMRV Scientific Research Working Group (SRWG)

Clin Vaccine Immunol 2011 May;18(5):825-34
In Vitro and In Vivo Studies of Monoclonal Antibodies with Prominent Bactericidal Activity against Burkholderia pseudomallei and Burkholderia mallei.
Zhang S, Feng SH, Li B, Kim HY, Rodriguez J, Tsai S, Lo SC

PLoS One 2011 May 9;6(5):e19867
Production and Characterization of Chimeric Monoclonal Antibodies against Burkholderia pseudomallei and B. mallei Using the DHFR Expression System.
Kim HY, Tsai S, Lo SC, Wear DJ, Izadjoo MJ

Oncotarget 2011 May;2(5):352-5
Mycoplasmas and human prostate cancer: an exciting but cautionary note.
Lo SC, Tsai S

Transfusion 2011 Mar;51(3):643-53
The Blood Xenotropic Murine Leukemia Virus-Related Virus Scientific Research Working Group: mission, progress, and plans.
Simmons G, Glynn SA, Holmberg JA, Coffin JM, Hewlett IK, Lo SC, Mikovits JA, Switzer WM, Linnen JM, Busch MP, Blood XMRV Scientific Research Working Group

J Virol 2011 Mar;85(6):2620-30
Kaposi's sarcoma-associated herpesvirus ORF57 promotes escape of viral and human interleukin-6 from microRNA-mediated suppression.
Kang JG, Pripuzova N, Majerciak V, Kruhlak M, Le SY, Zheng ZM

Proc Natl Acad Sci U S A 2010 Sep 7;107(36):15874-9
Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors.
Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ

J Biol Chem 2010 Jul 23;285(30):23359-70
The TOR complex 1 is distributed in endosomes and in retrograde vesicles that form from the vacuole membrane and plays an important role in the vacuole import and degradation pathway.
Brown CR, Hung GC, Dunton D, Chiang HL

     
 

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