April 18, 17
Recently, we and others have developed a markedly improved humanized mouse model of HIV by transplanting human CD34+ stem cells and autologous human thymic grafts into immunodeficient mice (see the article Brainard DM et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice).
The Ragon Institute Human Immune System Mouse Program was established in order to further develop this model, and to make it available to the wider Ragon and the broad HIV research community. Highly experienced personnel produce these animals and perform experiments in collaboration with Ragon investigators, as well as in collaboration with non-Ragon HIV investigators throughout the USA and countries around world.
The Human Immune System Mouse Program (HISMP) offers several different versions of humanized mice, useful for a broad array of investigations into human disease. For collaborating investigators, the HMP will generate humanized mice, perform models of human diseases (most commonly but not exclusively HIV infection), and acquire blood and tissue samples, as directed by collaborating investigators, for transfer and analyses in their laboratories.
Humanized mouse models provided:
- BLT (Bone Marrow-Liver-Thymus) mice: These mice are generated by adoptive transfer of human CD34+ stem cells, and transplantation of autologous human thymic grafts, into immunodeficient mice. This version of humanized mice have the most functional human immune systems, and is illustrated in the article: “Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice” by Brainard, et al.
- Hu-HSC mice: These mice are generated by adoptive transfer of human CD34+ stem cells into immunodeficient mice.
- Hu-PBL mice: These mice are generated by adoptive transfer of human peripheral blood leukocytes into immunodeficient mice.
- Hu-CD4+ mice: These mice are generated by adoptive transfer of purified human CD4+ T cells into immunodeficient mice.
Services Performed: Based on the experimental designs of collaborating investigators, HMP personnel will perform various mouse models of human disease, most commonly but not exclusively HIV infection. Access to BL3 vivarium space permits modeling of mTB infection as well. All handling of the mice, including all infections with HIV (by parenteral, intravaginal or intrarectal challenge) or other pathogens, immunizations or drug administration, and all pre-mortem blood specimen collections and post-mortem blood and tissue collections, will be performed by HMP personnel. Tissue specimens collected can include spleen, lymph nodes, bone marrow, lung, liver, brain, GI tract and GU tract. Pre-mortem surgical manipulations of the mice can be arranged through discussion with the HMP Associate Director.
Please note that our surgical capabilities are larger than stated on the HMP Fee Schedule. We are able to perform new, original surgery-related experiments, that are not specified on the price list. Arrangements for this can also be discussed with the HMP Associate Director.
Analyses: All samples will be provided to collaborating investigators for analyses in their laboratories. Investigators can make arrangements with the Ragon Institute Virology Core to have viral load determinations and/or viral sequencing analyses performed on plasma and/or tissue samples from those experiments. In those cases, the HMP will deliver samples to the Ragon Virology Core as directed. HMP personnel can also perform flow cytometry to measure CD3+, CD4+ and CD8+ T cell counts and CD19+ B cell counts on blood samples.
Sample shipments: The HMP sends and receives shipments from the Ragon Institute of MGH, MIT and Harvard. For shipments sent to the HMP, our shipping address is:
Dr. Vladimir Vrbanac
Ragon Institute of MGH, MIT and Harvard
400 Technology Square
Cambridge, MA 02139
All shipments sent or received by the HMP must follow the Standard Operating Procedure that governs the safe and compliant transport and shipment of all research samples coming in and going out of the Ragon Institute, as specified in: TRANSPORTATION AND SHIPMENT OF SAMPLES IN AND OUT RAGON_JUNE_2013 (pdf)
Grants: The HMP has successfully supported many grant applications to the NIH and other funding agencies for collaborating investigators. Investigators considering submission of a grant application including humanized mouse experiments are encouraged to contact the HMP Director for support of those applications. Applications for grants that will be administered at MGH can be supported with a letter of support from the HMP Director. Applications for grants that will administered at any non-MGH institution need to be supported by a subcontract to the HMP that need to be signed off by MGH Research Management. To allow for this approval, subcontracts need to be submitted to MGH Research Management 10 business days prior to the grant deadline. Collaborating investigators from non-MGH institutions therefore need to contact the HMP Director well ahead of their deadline when writing grant applications that propose experiments with HMP humanized mice.
The humanized mouse platform has an active “blanket” Institutional Animal Care and Use Committee (IACUC) protocol that covers the generation of the BLT mice, and outlines the general framework of most types of experiments anticipated, e.g. assessments of candidate vaccine immunogenicity and/or efficacy, assessments of the efficacy of novel anti-viral therapeutics, and assessments of the effects of the genetic manipulation of human hematopoietic stem cells prior to use to generate BLT mice. Each individual project selected to be performed will require IACUC approval of an amendment to the Program’s protocol. Program personnel, with the input of the collaborating investigator(s), will submit the required amendment to describe the specific experiments that will be performed as part of that individual project.
Because of the complexity of the model, the desire to maintain consistency, and the experience required for the safe handling of HIV-infected animals, IACUC protocols will be held by the Program’s directors. The BLT mice will be housed in the Program’s facilities and will be handled by the Program’s personnel. If collaborating investigators wish to house and handle BLT mice in their own animal facilities, potential exceptions to these policies can be discussed with the Program directors on a case-by-case basis.
Publications: A list of publications the HMP has collaborated on can be found here: http://www.ncbi.nlm.nih.gov/pubmed/?term=tager+am[au]+humanized+mouse
Because the HMP Director and Associate Director work closely with investigators in the design, performance, analyses and description of all humanized mouse experiments, we ask to be recognized as co-authors on publications including these experiments.
Prices: A list of prices for the generation of the various types of humanized mice, and for the procedures performed on them, by the HMP are contained in this HISMP Fee Schedule (PDF).
Payments: Payments for mice purchased are due prior to the initiation of experiments with them. Payments for procedures performed on mice in the course of experiments are due upon completion of the experiments. Collaborating investigators whose funds are at Partners Healthcare institutions can simply designate a fund number for costs to be applied to. Collaborating investigators at non-Partners institutions can either send a check or a purchase order number. Payment questions can be addressed to Karla Murga, HMP administrator.
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