Strain Name:

FVB-Tg(H2-D-Il15)3304Clgr/J

Stock Number:

006125

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Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Coisogenic; Mutant Strain; Transgenic;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Specieslaboratory mouse
GenerationN12pN1
Generation Definitions
 
Donating Investigator Michael A. Caligiuri,   The Ohio State University

Description
Mice hemizygous for this transgene are viable and fertile. The transgene was designed to optimize the overexpression of secreted, mature interleukin-15. Transgenic IL-15 expression has a similar tissue distribution as the endogenous gene, but at a significantly higher level. IL-15 protein is detectable in the serum from most mutant, but not from wildtype, mice. Mutant mice develop a progressive alopecia by as early as 5-6 weeks of age, with skin lesions appearing over time. While all transgenic mice exhibit early polyclonal/benign expansion of natural killer and memory CD8+ T lymphocytes (T/NK), two distinct phenotypes emerge over time: approximately 70% of the transgenic mice will exhibit polyclonal T/NK progression in multiple tissues, while the remaining 30% are characterized by T/NK clonal expansion in multiple tissues and acute lymphoblastic leukemia (T/NK ALL). Both T/NK phenotypes are fatal within the first year of life. Mice harboring this transgene may be useful in studies related to leukemia, lymphocyte homeostasis, alopecia, and graft-versus-host disease, or as a "pre-leukemia" model to elucidate the role of pro-inflammatory cytokine expression/chronic inflammation in transformation and malignancy.

Development
A mouse interleukin-15 cDNA sequence encoding the mature endogenous protein (nucleotides 610-951) was modified with a C-terminal FLAG epitope. This sequence was then fused immediately downstream of (and in-frame with) the mouse interleukin-2 signal peptide coding sequence. Next, the 3' portion of the human growth hormone (hGH) was spliced downstream and out of frame to maximize transgenic expression in vivo. This entire construct was placed under the control of the mouse MHC class 1 Dd promoter. The resulting 5.2 kb construct was injected into the pronucleus of FVB/N embryos. Embryos were transferred into the oviducts of pseudopregnant ICR foster mothers. Transgenic offspring were bred together for an unknown number of generations before arrival at The Jackson Laboratory.

Control Information

  Control
   Noncarrier
   001800 FVB/NJ
 
  Considerations for Choosing Controls

Related Strains

View Strains carrying other alleles of H2-D     (4 strains)

Strains carrying other alleles of Il15
010901   B6.Cg-Tg(ACTA1-Il15)10941Lsq/J
011002   B6.Cg-Tg(ACTA1-Il15*)11650Lsq/J
View Strains carrying other alleles of Il15     (2 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Tg(H2-D-Il15)3304Clgr/?

        FVB/N-Tg(H2-D-Il15)3304Clgr
  • mortality/aging
  • premature death
    • between 12 and 30 weeks of age, 70% of transgenic mice exhibit signs of illness - decreased activity, weight loss and breathing difficulty - and within a week become acutely moribund and die or must be euthanized   (MGI Ref ID J:67478)
  • immune system phenotype
  • abnormal T cell morphology
    • the early, benign expansion of CD8+CD44hiLy6c+ T cells observed in all transgenic mice is of polyclonal origin   (MGI Ref ID J:67478)
    • whereas absolute numbers of peripheral CD4+ T cells are comparable in 6 week old transgenic and control littermates, the number of CD8+ T cells is 10-fold greater in transgenic than in control mice   (MGI Ref ID J:67478)
    • flow cytometric analysis of lymphocytes from 22 affected (moribund) mice revealed the expanded population consistently bears the (somewhat heterogeneous) marker signature: CD3+TCR-beta+CD2+CD5+CD44+CD8+/-DX5mixed, although DX5+CD3- NK cells remain elevated   (MGI Ref ID J:67478)
    • abnormal T cell subpopulation ratio
      • because of the expansion of the CD8+ T cell compartment, the ratio of CD4+ to CD8+ T cells is dramatically skewed toward the CD8+ population in transgenic mice (0.59 +/- 0.04 versus 3.26 +/- 0.1 in controls)   (MGI Ref ID J:67478)
    • increased memory T cell number
      • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44hi CD62LloCD69-Ly6chi   (MGI Ref ID J:67478)
  • abnormal inflammatory response
    • large numbers of both CD3+ T lymphocytes and NK cells invade the spleens of ill mice   (MGI Ref ID J:67478)
    • dermatitis
      • mice with highly elevated lymphocyte counts exhibit skin inflammation characterized by heavy infiltration of the skin, primarily the dermis, by CD3+ lymphocytes and by mast cell infiltration   (MGI Ref ID J:67478)
  • abnormal lymphocyte physiology
    • transgenic mice that do not exhibit late clonal lymphocyte expansion nonetheless develop multiorgan lymphocytic infiltration   (MGI Ref ID J:67478)
    • mice with highly elevated lymphocyte counts have lymphocyte infiltration of the peritoneum and intraabdominal organs   (MGI Ref ID J:67478)
  • enlarged lymph nodes
    • mice with highly elevated lymphocyte counts have lymphadenopathy with disruption of the normal nodal architecture   (MGI Ref ID J:67478)
  • enlarged spleen
    • moribund mice have massive splenomegaly   (MGI Ref ID J:67478)
  • increased lymphocyte cell number
    • by 6 weeks of age, all transgenic mice exhibit peripheral blood lymphocytosis, with lymphocyte counts averaging 31, 694 +/- 3, 267 /ul of blood versus 7, 983 +/- 503/ ul of control blood   (MGI Ref ID J:67478)
    • between 12 and 30 weeks of age, 70% of transgenic mice demonstrate progression of earlier lymphocytosis, with lymphocyte counts averaging 186,000 +/- 32,433/ul (range 46,000 - 606,000/ul) of blood   (MGI Ref ID J:67478)
    • peripheral blood smears from ill mice contain large numbers of lymphocytes, some with blast-like features and prominent nucleoli   (MGI Ref ID J:67478)
    • increased NK cell number
      • early lymphocytosis in transgenic mice is due to expansion primarily of functional - in terms of target cell lysis and induced interferon gamma secretion - DX5+CD3-Ly49+ natural killer (NK) cells   (MGI Ref ID J:67478)
    • increased memory T cell number
      • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44hi CD62LloCD69-Ly6chi   (MGI Ref ID J:67478)
  • increased spleen white pulp amount
    • mice with highly elevated lymphocyte counts have expansion of the splenic white pulp   (MGI Ref ID J:67478)
  • hematopoietic system phenotype
  • abnormal T cell morphology
    • the early, benign expansion of CD8+CD44hiLy6c+ T cells observed in all transgenic mice is of polyclonal origin   (MGI Ref ID J:67478)
    • whereas absolute numbers of peripheral CD4+ T cells are comparable in 6 week old transgenic and control littermates, the number of CD8+ T cells is 10-fold greater in transgenic than in control mice   (MGI Ref ID J:67478)
    • flow cytometric analysis of lymphocytes from 22 affected (moribund) mice revealed the expanded population consistently bears the (somewhat heterogeneous) marker signature: CD3+TCR-beta+CD2+CD5+CD44+CD8+/-DX5mixed, although DX5+CD3- NK cells remain elevated   (MGI Ref ID J:67478)
    • abnormal T cell subpopulation ratio
      • because of the expansion of the CD8+ T cell compartment, the ratio of CD4+ to CD8+ T cells is dramatically skewed toward the CD8+ population in transgenic mice (0.59 +/- 0.04 versus 3.26 +/- 0.1 in controls)   (MGI Ref ID J:67478)
    • increased memory T cell number
      • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44hi CD62LloCD69-Ly6chi   (MGI Ref ID J:67478)
  • abnormal lymphocyte physiology
    • transgenic mice that do not exhibit late clonal lymphocyte expansion nonetheless develop multiorgan lymphocytic infiltration   (MGI Ref ID J:67478)
    • mice with highly elevated lymphocyte counts have lymphocyte infiltration of the peritoneum and intraabdominal organs   (MGI Ref ID J:67478)
  • enlarged spleen
    • moribund mice have massive splenomegaly   (MGI Ref ID J:67478)
  • increased bone marrow cell number
    • large numbers of both CD3+ T lymphocytes and NK cells invade the bone marrow of ill mice   (MGI Ref ID J:67478)
  • increased lymphocyte cell number
    • by 6 weeks of age, all transgenic mice exhibit peripheral blood lymphocytosis, with lymphocyte counts averaging 31, 694 +/- 3, 267 /ul of blood versus 7, 983 +/- 503/ ul of control blood   (MGI Ref ID J:67478)
    • between 12 and 30 weeks of age, 70% of transgenic mice demonstrate progression of earlier lymphocytosis, with lymphocyte counts averaging 186,000 +/- 32,433/ul (range 46,000 - 606,000/ul) of blood   (MGI Ref ID J:67478)
    • peripheral blood smears from ill mice contain large numbers of lymphocytes, some with blast-like features and prominent nucleoli   (MGI Ref ID J:67478)
    • increased NK cell number
      • early lymphocytosis in transgenic mice is due to expansion primarily of functional - in terms of target cell lysis and induced interferon gamma secretion - DX5+CD3-Ly49+ natural killer (NK) cells   (MGI Ref ID J:67478)
    • increased memory T cell number
      • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44hi CD62LloCD69-Ly6chi   (MGI Ref ID J:67478)
  • increased spleen white pulp amount
    • mice with highly elevated lymphocyte counts have expansion of the splenic white pulp   (MGI Ref ID J:67478)
  • tumorigenesis
  • increased leukemia incidence
    • molecular analysis of Tcrb gene rearrangements defined the late expanded lymphocyte populations of 48% (9/19) of ill transgenic mice as clonal, indicative of T-cell leukemia   (MGI Ref ID J:67478)
    • flow cytometric analysis of lymphocytes from 2 affected (moribund) mice revealed an expanded population of CD3-TCR-beta-CD8-CD4-DX5+ cells proposed to represent NK cell leukemias   (MGI Ref ID J:67478)
    • ~30% of transgenic mice develop clonal expansion of NK/T lymphocytes in multiple tissues that progresses to acute lymphoblastic leukemia (NK/T ALL)   (MGI Ref ID J:97873)
  • liver/biliary system phenotype
  • abnormal liver morphology
    • mice with highly elevated lymphocyte counts have liver involvement characterized by perivascular and sinusoidal lymphocyte infiltration   (MGI Ref ID J:67478)
    • enlarged liver
      • moribund mice have massive hepatomegaly   (MGI Ref ID J:67478)
  • respiratory system phenotype
  • abnormal lung morphology
    • mice with highly elevated lymphocyte counts have lung involvement ranging from heavy but confined infiltration around blood vessels to generalized infiltration involving the alveolar walls   (MGI Ref ID J:67478)
  • integument phenotype
  • alopecia
    • all mice with this transgene develop progressive alopecia beginning at 4-6 weeks of age, affecting initially the head and forelimbs and eventually 50-90% of the skin surface   (MGI Ref ID J:67478)
  • dermatitis
    • mice with highly elevated lymphocyte counts exhibit skin inflammation characterized by heavy infiltration of the skin, primarily the dermis, by CD3+ lymphocytes and by mast cell infiltration   (MGI Ref ID J:67478)
  • epidermal hyperplasia   (MGI Ref ID J:67478)
  • hair follicle degeneration   (MGI Ref ID J:67478)
  • hyperkeratosis   (MGI Ref ID J:67478)
  • spontaneous skin ulceration   (MGI Ref ID J:67478)
View Research Applications

Research Applications
This mouse can be used to support research in many areas including:

Cancer Research
Genes Regulating Growth and Proliferation
Growth Factors/Receptors/Cytokines
Increased Tumor Incidence
      Leukemia

Cardiovascular Research
Vascular Defects
      defective leukocyte function

Dermatology Research
Skin and Hair Texture Defects

Immunology, Inflammation and Autoimmunity Research
Growth Factors/Receptors/Cytokines
Immunodeficiency
      NK Cell and Cd8 T Cell defects

Internal/Organ Research
Lymphoid Tissue Defects

Research Tools
Cancer Research
      Leukemia
      xenograft/transplant host
Dermatology Research
Immunology, Inflammation and Autoimmunity Research
      T cell deficiency, xenograft/transplant host
Toxicology Research
      xenograft/transplant host

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Tg(H2-D-Il15)3304Clgr
Allele Name transgene insertion 3304, Michael A Caligiuri
Allele Type Transgenic (Inserted expressed sequence)
Common Name(s) Dd-IL-15; IL-15tg; IL15tg; Il15-Tg;
Mutation Made By Michael Caligiuri,   The Ohio State University
Strain of OriginFVB/N
Expressed Gene Il15, interleukin 15, mouse, laboratory
Promoter H2-D, histocompatibility 2, D region, mouse, laboratory
General Note Posttranscriptional checkpoints that maintain low endogenous wild-type IL15 intra- and extracellular protein levels - a series of 5' AUGs, the poorly translated and secreted IL15 signal peptide sequence and a C-terminal retention signal - have been eliminated from the transgene and replaced with sequences that maximize IL15 expression. (J:67478)

Although three transgenic lines were created in the FVB/N background, the phenotype is reported only for line 3304; the others are 3284 and 3285. It is stated that the phenotypes of all three are similar, but differ in severity depending on the level of transgene mRNA expression. (J:67478)

Molecular Note The coding region of the transgene comprises a cDNA encoding the mature mouse IL15 protein (nt 610-951) joined to the signal peptide-encoding sequence of the mouse IL2 gene (nt 49-108) and followed by a FLAG epitope tag coding sequence. Upstream of, andin frame with, the coding sequence is the nearly ubiquitously expressed promoter of the H2-Dd major histocompatibility class I gene, and downstream of and out of frame with it is the 3' end of the human growth hormone gene. RT-PCR and immunoblot analysis for the FLAG epitope detected high levels of mRNA and protein, respectively, in numerous tissues. Whereas IL15 is undetectable in sera of wild-type mice, measurable levels are present in ~75% of transgenic sera. [MGI Ref ID J:67478]
 
 

Genotyping

Genotyping Information

Genotyping Protocols

Tg(H2-D-Il15)3304Clgr, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Additional References

Tg(H2-D-Il15)3304Clgr related

Davies E; Reid S; Medina MF; Lichty B; Ashkar AA. 2010. IL-15 has innate anti-tumor activity independent of NK and CD8 T cells. J Leukoc Biol 88(3):529-36. [PubMed: 20538758]  [MGI Ref ID J:164922]

DePaolo RW; Abadie V; Tang F; Fehlner-Peach H; Hall JA; Wang W; Marietta EV; Kasarda DD; Waldmann TA; Murray JA; Semrad C; Kupfer SS; Belkaid Y; Guandalini S; Jabri B. 2011. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471(7337):220-4. [PubMed: 21307853]  [MGI Ref ID J:170338]

Fehniger TA; Suzuki K; Ponnappan A; VanDeusen JB; Cooper MA; Florea SM; Freud AG; Robinson ML; Durbin J; Caligiuri MA. 2001. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193(2):219-31. [PubMed: 11208862]  [MGI Ref ID J:67478]

Fehniger TA; Suzuki K; VanDeusen JB; Cooper MA; Freud AG; Caligiuri MA. 2001. Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 27(1):223-30. [PubMed: 11358383]  [MGI Ref ID J:69192]

French AR; Kim S; Fehniger TA; Pratt JR; Yang L; Song YJ; Caligiuri MA; Yokoyama WM. 2007. Chronic lymphocytosis of functionally immature natural killer cells. J Allergy Clin Immunol 120(4):924-31. [PubMed: 17604094]  [MGI Ref ID J:137640]

Liu RB; Engels B; Arina A; Schreiber K; Hyjek E; Schietinger A; Binder DC; Butz E; Krausz T; Rowley DA; Jabri B; Schreiber H. 2012. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res 72(8):1964-74. [PubMed: 22374983]  [MGI Ref ID J:185673]

Richards JO; Chang X; Blaser BW; Caligiuri MA; Zheng P; Liu Y. 2006. Tumor growth impedes natural-killer-cell maturation in the bone marrow. Blood 108(1):246-52. [PubMed: 16556890]  [MGI Ref ID J:135679]

Sissons J; Yan BS; Pichugin AV; Kirby A; Daly MJ; Kramnik I. 2009. Multigenic control of tuberculosis resistance: analysis of a QTL on mouse chromosome 7 and its synergism with sst1. Genes Immun 10(1):37-46. [PubMed: 18784733]  [MGI Ref ID J:153395]

Sunwoo JB; Kim S; Yang L; Naik T; Higuchi DA; Rubenstein JL; Yokoyama WM. 2008. Distal-less homeobox transcription factors regulate development and maturation of natural killer cells. Proc Natl Acad Sci U S A 105(31):10877-82. [PubMed: 18664585]  [MGI Ref ID J:139949]

Yu L; Liu C; Vandeusen J; Becknell B; Dai Z; Wu YZ; Raval A; Liu TH; Ding W; Mao C; Liu S; Smith LT; Lee S; Rassenti L; Marcucci G; Byrd J; Caligiuri MA; Plass C. 2005. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 37(3):265-74. [PubMed: 15723065]  [MGI Ref ID J:97873]

Zhao H; Nguyen H; Kang J. 2005. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nat Immunol 6(12):1263-71. [PubMed: 16273100]  [MGI Ref ID J:112655]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, these mice are bred as hemizygotes. The donating investigator reports that homozygous mice may be infertile, and carrier males may be hard to breed after 8 weeks of age. In addition, carrier mice can often be identified by early hair thinning, especially around the ears.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2140.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2782.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   Noncarrier
   001800 FVB/NJ
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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