Description

Strain Information

Former Names C57BL/6-Tg(BCL2)22Wehi/J    (Changed: 24-JAN-06 ) Type Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N28   Donating Investigator Alan Harris,   The Walter & Eliza Hall Inst of Med Res

Appearance
black
Related Genotype: a/a

Description
Expression of the human BCL2 transgene is restricted to B cell lineage (no T cell expression) in which it enhances cell survival. Hemizygotes show increased numbers of B lymphocytes, Ig-secreting cells and serum Ig, as well as a heightened and prolonged antibody response to immunization. This phenotype is somewhat greater on the BALB/c than on the C57BL/6 background. Hemizygotes on a mixed B6,SJL background (but not on the BALB/c background) develop autoimmune disease characterized by immune complex glomerulonephritis, anti-nuclear antibodies, lymphadenopathy and myocardial infarction. These mice serve as a robust source for the production of B cells and antibodies. Although mice bearing this allele exhibit a mild increase in spontaneous lymphoma and plasmacytoma occurrence (<10% to 18 months) on a (C57BL/6 x SJL)F2 background, on the BALB/c and C57BL/6 backgrounds tumor incidence is insignificant. When this transgene is crossed with an Emu-myc transgene bearing strain (Stock No. 002728), the resulting double transgenic develops primitive lymphoid tumors within 5 weeks.

Development
The TgN(BCL2)22Wehi transgenic strain was made in the laboratory of Dr. Alan Harris of the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. The transgene construct consisted of the human BCL2 cDNA in association with the Emu immunoglobulin heavy chain enhancer and SV40 promoter. Original background was mix of C57BL/6JWehi and SJL/JWehi. Transgenic mice have been bred to C57BL/6J more than 20 generations.

Control Information

	Control
	Noncarrier
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Tg(BCL2)22Wehi allele

002318

C.Cg-Tg(BCL2)22Wehi/J

View Strains carrying   Tg(BCL2)22Wehi     (1 strain)

Strains carrying other alleles of BCL2

002320	B6.Cg-Tg(BCL2)25Wehi/J
002321	B6.Cg-Tg(BCL2)36Wehi/J
002427	C3H/He-Tg(LCKprBCL2)36Sjk/J
002971	FVB-Tg(BCL2OVARY)1Ah/J

View Strains carrying other alleles of BCL2     (4 strains)

Strains carrying other alleles of SV40

002320	B6.Cg-Tg(BCL2)25Wehi/J
002321	B6.Cg-Tg(BCL2)36Wehi/J
003477	C57BL/6J-Tg(SV)419Bri/J
003476	C57BL/6J-Tg(SV)427Bri/J
003268	FVB-Tg(IRS1)1Mhep/J

View Strains carrying other alleles of SV40     (5 strains)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Tg(BCL2)22Wehi/0

        involves: C57BL/6JWehi * SJL/JWehi

• hematopoietic system phenotype
• abnormal B cell differentiation (MGI Ref ID J:93111)
  • most transgenic B cells are smaller than normal B cells
• increased B cell number (MGI Ref ID J:93111)
  • mutants show a 2- to 5-fold excess of B lymphocytes in spleen, lymph nodes, and bone marrow
• immune system phenotype
• abnormal B cell differentiation (MGI Ref ID J:93111)
  • most transgenic B cells are smaller than normal B cells
• abnormal B cell physiology (MGI Ref ID J:93111)
  • transgenic spleen B cells show prolonged in vitro survival in culture compared to wild-type splenocytes
• increased B cell number (MGI Ref ID J:93111)
  • mutants show a 2- to 5-fold excess of B lymphocytes in spleen, lymph nodes, and bone marrow
• increased susceptibility to autoimmune disorder (MGI Ref ID J:93111)
  • a portion of transgenic mice develop autoimmune-like disease

View Research Applications

Research Applications

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

Apoptosis Research
Endogenous Regulators

Cancer Research
Increased Tumor Incidence (Lymphomas)
Tumor Suppressor Genes

Immunology and Inflammation Research
Autoimmunity
Intracellular Signaling Molecules

Research Tools
Cancer Research (production of B cells and antibodies)
Immunology and Inflammation Research (production of B cells and antibodies)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(BCL2)22Wehi
Allele Name		transgene insertion 22, Walter and Eliza Hall Institute of Medical Research
Allele Type		Transgenic (random, expressed)
Common Name(s)		22Wehi; C-Emu-bcl-2-22; Emu-bcl-2; Emu-bcl-2-22;
Mutation Made By		Alan Harris,   The Walter & Eliza Hall Inst of Med Res
Strain of Origin		(C57BL/6JWehi x SJL/JWehi)F2
Expressed Gene		BCL2, B-cell CLL/lymphoma 2, human
Promoter		SV40, E mu enhancer, SV40
General Note		In transgenic mice on a C57BL/6 background, expression of the transgene is restricted to the B cell lineage (no T-cell expression).
Molecular Note		The transgene construct consists of the human BCL2 cDNA in association with the Emu immunoglobulin heavy chain enhancer and SV40 promoter. [MGI Ref ID J:93111]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(BCL2), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Strasser A; Whittingham S; Vaux DL; Bath ML; Adams JM; Cory S; Harris AW. 1991. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A 88(19):8661-5. [PubMed: 1924327]  [MGI Ref ID J:69562]

Additional References

Hess P; Pihan G; Sawyers CL; Flavell RA; Davis RJ. 2002. Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat Genet 32(1):201-5. [PubMed: 12161751]  [MGI Ref ID J:92945]

Kuroki A; Moll T; Lopez-Hoyos M; Fossati-Jimack L; Ibnou-Zekri N; Kikuchi S; Merino J; Merino R; Izui S. 2004. Enforced Bcl-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA production, but the Yaa mutation promotes only anti-DNA production. Eur J Immunol 34(4):1077-84. [PubMed: 15048718]  [MGI Ref ID J:88856]

O'Reilly LA; Harris AW; Tarlinton DM; Corcoran LM; Strasser A. 1997. Expression of a bcl-2 transgene reduces proliferation and slows turnover of developing B lymphocytes in vivo. J Immunol 159(5):2301-11. [PubMed: 9278319]  [MGI Ref ID J:93123]

Strasser A; Harris AW; Bath ML; Cory S. 1990. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348(6299):331-3. [PubMed: 2250704]  [MGI Ref ID J:69571]

Tg(BCL2)22Wehi related

Ait-Azzouzene D; Verkoczy L; Peters J; Gavin A; Skog P; Vela JL; Nemazee D. 2005. An immunoglobulin C{kappa}-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system. J Exp Med 201(5):817-28. [PubMed: 15738053]  [MGI Ref ID J:96759]

Allen CD; Okada T; Tang HL; Cyster JG. 2007. Imaging of germinal center selection events during affinity maturation. Science 315(5811):528-31. [PubMed: 17185562]  [MGI Ref ID J:118931]

Caucheteux SM; Gendron MC; Kanellopoulos-Langevin C. 2005. Pregnancy-induced alterations of B cell maturation and survival are differentially affected by Fas and Bcl-2, independently of BcR expression. Int Immunol 17(1):55-63. [PubMed: 15569774]  [MGI Ref ID J:94796]

Corcos D; Grandien A; Vazquez A; Dunda O; Lores P; Bucchini D. 2001. Expression of a V region-less B cell receptor confers a tolerance-like phenotype on transgenic B cells. J Immunol 166(5):3083-9. [PubMed: 11207259]  [MGI Ref ID J:133777]

Cory S; Harris AW; Strasser A. 1994. Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells. Philos Trans R Soc Lond B Biol Sci 345(1313):289-95. [PubMed: 7846127]  [MGI Ref ID J:21062]

Dierks C; Grbic J; Zirlik K; Beigi R; Englund NP; Guo GR; Veelken H; Engelhardt M; Mertelsmann R; Kelleher JF; Schultz P; Warmuth M. 2007. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 13(8):944-51. [PubMed: 17632527]  [MGI Ref ID J:126550]

Fokko van Loo P; Dingjan GM; Maas A; Hendriks RW. 2007. Surrogate-light-chain silencing is not critical for the limitation of pre-B cell expansion but is for the termination of constitutive signaling. Immunity 27(3):468-80. [PubMed: 17869135]  [MGI Ref ID J:125321]

Hu CJ; Rao S; Ramirez-Bergeron DL; Garrett-Sinha LA; Gerondakis S; Clark MR; Simon MC. 2001. PU.1/Spi-B regulation of c-rel is essential for mature B cell survival. Immunity 15(4):545-55. [PubMed: 11672537]  [MGI Ref ID J:93128]

Huang X; Di Liberto M; Cunningham AF; Kang L; Cheng S; Ely S; Liou HC; Maclennan IC; Chen-Kiang S. 2004. Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. Proc Natl Acad Sci U S A 101(51):17789-94. [PubMed: 15591344]  [MGI Ref ID J:95280]

Iwata A; Stevenson VM; Minard A; Tasch M; Tupper J; Lagasse E; Weissman I; Harlan JM; Winn RK. 2003. Over-expression of Bcl-2 provides protection in septic mice by a trans effect. J Immunol 171(6):3136-41. [PubMed: 12960340]  [MGI Ref ID J:85373]

Janas ML; Hodgkin P; Hibbs M; Tarlinton D. 1999. Genetic evidence for Lyn as a negative regulator of IL-4 signaling. J Immunol 163(8):4192-8. [PubMed: 10510355]  [MGI Ref ID J:106741]

Janssen EM; Droin NM; Lemmens EE; Pinkoski MJ; Bensinger SJ; Ehst BD; Griffith TS; Green DR; Schoenberger SP. 2005. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434(7029):88-93. [PubMed: 15744305]  [MGI Ref ID J:96586]

Kersseboom R; Ta VB; Zijlstra AJ; Middendorp S; Jumaa H; van Loo PF; Hendriks RW. 2006. Bruton's tyrosine kinase and SLP-65 regulate pre-B cell differentiation and the induction of Ig light chain gene rearrangement. J Immunol 176(8):4543-52. [PubMed: 16585544]  [MGI Ref ID J:131167]

Koralov SB; Muljo SA; Galler GR; Krek A; Chakraborty T; Kanellopoulou C; Jensen K; Cobb BS; Merkenschlager M; Rajewsky N; Rajewsky K. 2008. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 132(5):860-74. [PubMed: 18329371]  [MGI Ref ID J:135783]

Kuroki A; Moll T; Lopez-Hoyos M; Fossati-Jimack L; Ibnou-Zekri N; Kikuchi S; Merino J; Merino R; Izui S. 2004. Enforced Bcl-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA production, but the Yaa mutation promotes only anti-DNA production. Eur J Immunol 34(4):1077-84. [PubMed: 15048718]  [MGI Ref ID J:88856]

Kurtz BS; Witte PL; Storb U. 1997. Gamma 2b provides only some of the signals normally given via mu in B cell development. Int Immunol 9(3):415-26. [PubMed: 9088980]  [MGI Ref ID J:110626]

Lesage S; Steff AM; Philippoussis F; Page M; Trop S; Mateo V ; Hugo P. 1997. CD4+ CD8+ thymocytes are preferentially induced to die following CD45 cross-linking, through a novel apoptotic pathway. J Immunol 159(10):4762-71. [PubMed: 9366400]  [MGI Ref ID J:44075]

Marquina R; Diez MA; Lopez-Hoyos M; Buelta L; Kuroki A; Kikuchi S; Villegas J; Pihlgren M; Siegrist CA; Arias M; Izui S; Merino J; Merino R. 2004. Inhibition of B cell death causes the development of an IgA nephropathy in (New Zealand white x C57BL/6)F(1)-bcl-2 transgenic mice. J Immunol 172(11):7177-85. [PubMed: 15153542]  [MGI Ref ID J:90535]

Mathieu N; Spicuglia S; Gorbatch S; Cabaud O; Fernex C; Verthuy C; Hempel WM; Hueber AO; Ferrier P. 2003. Assessing the role of the T cell receptor beta gene enhancer in regulating coding joint formation during V(D)J recombination. J Biol Chem 278(20):18101-9. [PubMed: 12639959]  [MGI Ref ID J:83594]

Morales M; Theunissen JW; Kim CF; Kitagawa R; Kastan MB; Petrini JH. 2005. The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev 19(24):3043-54. [PubMed: 16357220]  [MGI Ref ID J:103922]

Otero DC; Anzelon AN; Rickert RC. 2003. CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals. J Immunol 170(1):73-83. [PubMed: 12496385]  [MGI Ref ID J:127029]

Otipoby KL; Sasaki Y; Schmidt-Supprian M; Patke A; Gareus R; Pasparakis M; Tarakhovsky A; Rajewsky K. 2008. BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells. Proc Natl Acad Sci U S A 105(34):12435-8. [PubMed: 18713867]  [MGI Ref ID J:138966]

Pan C; Baumgarth N; Parnes JR. 1999. CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity 11(4):495-506. [PubMed: 10549631]  [MGI Ref ID J:76990]

Rietz C; Screpanti V; Brenden N; Bohme J; Fernandez C. 2003. Overexpression of bcl-2 in T cells affects insulitis in the nonobese diabetic mouse. Scand J Immunol 57(4):342-9. [PubMed: 12662297]  [MGI Ref ID J:131889]

Rietz C; Screpanti V; Brenden N; Fernandez C. 2001. Neonatal pattern of V(H) gene utilization in nonobese diabetic mice does not correlate with development of insulitis. Scand J Immunol 54(5):470-6. [PubMed: 11696198]  [MGI Ref ID J:133860]

Rolink AG; Winkler T; Melchers F; Andersson J. 2000. Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J Exp Med 191(1):23-32. [PubMed: 10620602]  [MGI Ref ID J:112418]

Sapoznikov A; Pewzner-Jung Y; Kalchenko V; Krauthgamer R; Shachar I; Jung S. 2008. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat Immunol 9(4):388-95. [PubMed: 18311142]  [MGI Ref ID J:133263]

Sasaki Y; Casola S; Kutok JL; Rajewsky K; Schmidt-Supprian M. 2004. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. J Immunol 173(4):2245-52. [PubMed: 15294936]  [MGI Ref ID J:92732]

Sasaki Y; Derudder E; Hobeika E; Pelanda R; Reth M; Rajewsky K; Schmidt-Supprian M. 2006. Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24(6):729-39. [PubMed: 16782029]  [MGI Ref ID J:113365]

Stoddart A; Fleming HE; Paige CJ. 2001. The role of homotypic interactions in the differentiation of B cell precursors. Eur J Immunol 31(4):1160-72. [PubMed: 11298341]  [MGI Ref ID J:92949]

Strasser A; Elefanty AG; Harris AW; Cory S. 1996. Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival. EMBO J 15(15):3823-34. [PubMed: 8670887]  [MGI Ref ID J:34979]

Strasser A; Harris AW; Bath ML; Cory S. 1990. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348(6299):331-3. [PubMed: 2250704]  [MGI Ref ID J:69571]

Strasser A; Harris AW; Cory S. 1993. E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene 8(1):1-9. [PubMed: 8423986]  [MGI Ref ID J:102056]

Strasser A; Harris AW; Cory S. 1991. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67(5):889-99. [PubMed: 1959134]  [MGI Ref ID J:69572]

Strasser A; Harris AW; Vaux DL; Webb E; Bath ML; Adams JM; Cory S. 1990. Abnormalities of the immune system induced by dysregulated bcl-2 expression in transgenic mice. Curr Top Microbiol Immunol 166:175-81. [PubMed: 2073796]  [MGI Ref ID J:93111]

Takahashi Y; Inamine A; Hashimoto S; Haraguchi S; Yoshioka E; Kojima N; Abe R; Takemori T. 2005. Novel role of the Ras cascade in memory B cell response. Immunity 23(2):127-38. [PubMed: 16111632]  [MGI Ref ID J:100532]

Tardivel A; Tinel A; Lens S; Steiner QG; Sauberli E; Wilson A; Mackay F; Rolink AG; Beermann F; Tschopp J; Schneider P. 2004. The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF. Eur J Immunol 34(2):509-18. [PubMed: 14768056]  [MGI Ref ID J:87673]

Tirosh B; Iwakoshi NN; Glimcher LH; Ploegh HL. 2005. XBP-1 specifically promotes IgM synthesis and secretion, but is dispensable for degradation of glycoproteins in primary B cells. J Exp Med 202(4):505-16. [PubMed: 16103408]  [MGI Ref ID J:100496]

Torres RM; Hafen K. 1999. A negative regulatory role for Ig-alpha during B cell development. Immunity 11(5):527-36. [PubMed: 10591178]  [MGI Ref ID J:110760]

Tze LE; Schram BR; Lam KP; Hogquist KA; Hippen KL; Liu J; Shinton SA; Otipoby KL; Rodine PR; Vegoe AL; Kraus M; Hardy RR; Schlissel MS; Rajewsky K; Behrens TW. 2005. Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol 3(3):e82. [PubMed: 15752064]  [MGI Ref ID J:133822]

Van Parijs L; Peterson DA; Abbas AK. 1998. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity 8(2):265-74. [PubMed: 9492007]  [MGI Ref ID J:110425]

Vela JL; Ait-Azzouzene D; Duong BH; Ota T; Nemazee D. 2008. Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production. Immunity 28(2):161-70. [PubMed: 18261939]  [MGI Ref ID J:132125]

Vigorito E; Gambardella L; Colucci F; McAdam S; Turner M. 2005. Vav proteins regulate peripheral B-cell survival. Blood 106(7):2391-8. [PubMed: 15941910]  [MGI Ref ID J:119378]

Wikstrom I; Bergqvist I; Holmberg D; Forssell J. 2006. Dmu expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2. Mol Immunol 43(9):1316-24. [PubMed: 16321440]  [MGI Ref ID J:108122]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain is maintained by mating hemizygous mice with wildtype siblings. Expected coat color from breeding:Black
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Noncarrier
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Ordering and Purchasing Information

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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.