Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation N7+F5 (19-AUG-08)   Donating Investigator Kazue Takahashi,   Massachusetts General Hospital

Description
Mice homozygous for both mannose-binding lectin (MBL)-A and MBL-C targeted mutations (termed MBL-null) are viable, fertile, and normal in size with no obvious developmental defects. Histological examination of multiple organs from 6-10 week old mice shows no abnormalities. MBL-null mice have no endogenous gene expression in liver (the principal site of MBL synthesis) and no protein detectable in serum. While the classical complement pathway is unaffected in MBL-null mice, the lectin-dependent complement pathway is non-functional. MBL-null mice have increased mortality following intravenous injection of S. aureus associated with abnormal serum levels of TNFalpha and IL-6 (decreased at 2h, elevated at 24h post injection). Cyclophosphamide-induced febrile neutropenic MBL-null mice inoculated with S. aureus have greatly increased susceptibility to abscess formation in kidney, liver, and lung (but not spleen). These same treated mice also have persistent bacteremia despite a recovery of circulating neutrophils and reduction of both circulating monocytes and resident peritoneal macrophages. Resident peritoneal macrophages harvested following intraperitoneal injection of S. aureus have impaired bacterial phagocytosis. MBL-null mice have an expansion of peritoneal B1 cells but a decreased splenic B cell p opulation. Double mutant mice have defective apoptotic cell clearance with no autoimmune phenotype out to 18 months of age. MBL-null mice have increased susceptibility to postburn infection with P. aeruginosa and defective hepatic clearance of virus following herpes simplex virus-2 injection. Double mutant mice insulted with gastrointestinal ischemia/reperfusion (I/R) are protected from intestinal, but not secondary lung, injury and C3 accumulation. Mutant mice are also protected from injury and C3 accumulation following bilateral renal I/R and myocardial I/R. These mice may be useful in studies of host defense, including inflammation and infection, chemotherapy-induced neutropenia, apoptosis, and I/R models of the complement pathway.

Development
A targeting vector was designed to insert a neomycin resistance gene into exon 5 of the MBL-A (Mbl1) gene. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were microinjected into C57BL/6J blastocysts and chimeric offspring were bred with C57BL/6J mice for multiple generations and then made homozygous. Independently, a construct was designed to replace exon 6 of the MBL-C (Mbl2) gene with a neomycin resistance gene. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were microinjected into C57BL/6J blastocysts. Chimeric offspring were bred to make homozygous mutant mice. To generate mice homozygous for both mutations (MBL-null), MBL-A mutant homozygotes were bred with homozygous MBL-C mutant mice. Double mutant mice were backcrossed to C57BL/6J for 7 generations before being made homozygous.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

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.

Mbl1^tm1Kata/Mbl1^tm1Kata Mbl2^tm1Kata/Mbl2^tm1Kata

        involves: 129 * C57BL/6

• immune system phenotype
• abnormal B cell number (MGI Ref ID J:97686)
• decreased germinal center B cell number (MGI Ref ID J:97686)
  • more than 60% decrease in germinal center B cell numbers
• increased B-1 B cell number (MGI Ref ID J:97686)
  • increased number of peritoneal B1 cells, however no lymphoproliferation occurred
• abnormal circulating interleukin-6 level (MGI Ref ID J:98124)
  • serum IL-6 levels were reduced at 2 hours after S. aureus inoculation, however levels were increased 8-fold at 24 hours after inoculation compared to wildtype
• abnormal circulating tumor necrosis factor level (MGI Ref ID J:98124)
  • serum TNF-alpha levels were reduced at 2 hours after S. aureus inoculation, however levels were increased 15-fold at 24 hours after inoculation compared to wildtype
• decreased macrophage cell number (MGI Ref ID J:98124)
  • double homozygous mutants rendered neutropenic by cyclophosphamide (CY) injection had an 80% decrease in resident peritoneal macrophages
• decreased monocyte cell number (MGI Ref ID J:98124)
  • double homozygous mutants rendered neutropenic by cyclophosphamide (CY) injection had an 80% decrease in circulating monocytes
• impaired macrophage phagocytosis (MGI Ref ID J:97686)
  • demonstrated defective apoptotic cell clearance (16% of macrophages phagocytosed compared to more than 25% in wildtype), however did not develop spontaneous autoimmunity
  • 38% decrease in percentage of phagocytic cells
  • showed a 40% reduction in bacterial phagocytosis by resident peritoneal macrophages
• increased susceptibility to bacterial infection (MGI Ref ID J:98124)
  • 100% of double mutants died 48 hours after S. aureus infection compared to 45% of wildtype
  • statistically significant higher bacterial loads were found in the kidney, spleen, liver and blood compared with wildtype at 24 hours after S. aureus inoculation
  • double homozygous mutants rendered neutropenic by cyclophosphamide (CY) injection exhibited increased susceptibility to bacterial infection with 21/29 developing abscesses in various organs compared to 3/15 of wildtype
• hematopoietic system phenotype
• abnormal B cell number (MGI Ref ID J:97686)
• decreased germinal center B cell number (MGI Ref ID J:97686)
  • more than 60% decrease in germinal center B cell numbers
• increased B-1 B cell number (MGI Ref ID J:97686)
  • increased number of peritoneal B1 cells, however no lymphoproliferation occurred
• decreased macrophage cell number (MGI Ref ID J:98124)
  • double homozygous mutants rendered neutropenic by cyclophosphamide (CY) injection had an 80% decrease in resident peritoneal macrophages
• decreased monocyte cell number (MGI Ref ID J:98124)
  • double homozygous mutants rendered neutropenic by cyclophosphamide (CY) injection had an 80% decrease in circulating monocytes
• homeostasis/metabolism phenotype
• abnormal circulating interleukin-6 level (MGI Ref ID J:98124)
  • serum IL-6 levels were reduced at 2 hours after S. aureus inoculation, however levels were increased 8-fold at 24 hours after inoculation compared to wildtype
• abnormal circulating tumor necrosis factor level (MGI Ref ID J:98124)
  • serum TNF-alpha levels were reduced at 2 hours after S. aureus inoculation, however levels were increased 15-fold at 24 hours after inoculation compared to wildtype

Mbl1^tm1Kata/Mbl1^tm1Kata Mbl2^tm1Kata/Mbl2^tm1Kata

        involves: 129/Sv * C57BL/6J

• immune system phenotype
• abnormal complement physiology (MGI Ref ID J:106351)
  • after 45 min ischemia followed by 2 h reperfusion, complement activation as assessed by plasma C3a (desArg) level is significantly greater in wild-type mice than in double homozygous mutants; by 24 h, both groups have C3a levels < 30 ng/ml
• abnormal response to infection (MGI Ref ID J:106352)
  • doubly homozygous mutant mice infected intraperitoneally with herpes simplex virus type II (HSV-2) begin to clear the infection more slowly from the liver than do wild-type mice; however, complete clearance occurs in both by 6 days post-infection
  • the proportion of HSV-2 neutralized in vitro after 9 minutes' exposure to serum from double homozygotes is significantly lower than after incubation with serum from wild-type mice; however, both have neutralized 90% of virus after > 21 minutes
• increased susceptibility to bacterial infection (MGI Ref ID J:106353)
  • all doubly homozygous mutant mice, but only 30% of wild-type mice, die within 42 h after burning of 5% of total body surface area (TBSA) followed by subcutaneous (s.c.) inoculation with Pseudomonas aeruginosa, whereas neither mutant nor wild-type mice appear ill following either treatment alone
  • P. aeruginosa titers in plasma and homogenates of blood, liver and kidney harvested 20 h after the postburn inoculation are significantly higher in double homozygous than in wild-type mice; however, titers in lung and in skin do not differ significantly
• renal/urinary system phenotype
• decreased susceptibility to kidney reperfusion injury (MGI Ref ID J:106351)
  • doubly homozygous mutant mice exhibit significantly less elevation of blood urea nitrogen (BUN) levels than do wild-type mice following induction of bilateral kidney eschemia (45 min) and reperfusion (24 h)
  • after 45 min ischemia followed by 2 or 24 h reperfusion, histological examination of wild-type kidneys reveals severe tubular damage characterized by dilation, necrosis and presence of proteinaceous casts; kidneys of double homozygous mice exhibit no such damage

View Research Applications

Research Applications

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

Cancer Research
Other

Cardiovascular Research
Ischemia studies

Immunology and Inflammation Research
Autoimmunity (specific complement deficiency)
CD Antigens, Antigen Receptors, and Histocompatibility Markers (genes regulating susceptibility to infectious disease and endotoxin)
Immunodeficiency (defects in humoral immune responses)
Immunodeficiency (multiple immune defects)
Immunodeficiency (specific complement deficiency)
Immunodeficiency Associated with Other Defects

Research Tools
Apoptosis Research
Cancer Research
Immunology and Inflammation Research (genes regulating susceptibility to infectious disease and endotoxin)
Immunology and Inflammation Research (specific complement deficiency)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Mbl1tm1Kata
Allele Name		targeted mutation 1, Kazue Takahashi
Allele Type		Targeted (knock-out)
Common Name(s)		MBL-A-;
Mutation Made By		Kazue Takahashi,   Massachusetts General Hospital
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Mbl1, mannose-binding lectin (protein A) 1
Chromosome		14
Gene Common Name(s)		MBL-A; MBP-A; Mbpa; Mlb1;
Molecular Note		Exon 5 was disrupted by the insertion of a neomycin selection cassette into sequence encoding the carbohydrate recognition domain. Transcript was undetected by RT-PCR analysis of liver RNA obtained from homozygous mutant mice. RT-PCR analysis indicated that transcription of the paralogous Mbl2 gene was unaffected. [MGI Ref ID J:90437]
Allele Symbol		Mbl2tm1Kata
Allele Name		targeted mutation 1, Kazue Takahashi
Allele Type		Targeted (knock-out)
Common Name(s)		MBL-C KO;
Mutation Made By		Kazue Takahashi,   Massachusetts General Hospital
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Mbl2, mannose-binding lectin (protein C) 2
Chromosome		19
Gene Common Name(s)		COLEC1; HSMBPC; MBL; MBL-C; MBP; MBP-C; MBP1; MGC116832; MGC116833;
Molecular Note		The gene was disrupted by the insertion of a neomycin resistance gene into exon 6. RT-PCR analysis demonstrated the lack of transcript in mutant liver. [MGI Ref ID J:98124]

Genotyping

Genotyping Information

Genotyping Protocols

Mbl1^tm1Kata, STD PCR, vers. 1
Mbl2^tm1Kata, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Shi L; Takahashi K; Dundee J; Shahroor-Karni S; Thiel S; Jensenius JC; Gad F; Hamblin MR; Sastry KN; Ezekowitz RA. 2004. Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus. J Exp Med 199(10):1379-90. [PubMed: 15148336]  [MGI Ref ID J:98124]

Additional References

Mbl1^tm1Kata related

Busche MN; Walsh MC; McMullen ME; Guikema BJ; Stahl GL. 2008. Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes. Diabetologia 51(8):1544-51. [PubMed: 18493734]  [MGI Ref ID J:137894]

Chan RK; Ibrahim SI; Takahashi K; Kwon E; McCormack M; Ezekowitz A; Carroll MC; Moore FD Jr; Austen WG Jr. 2006. The differing roles of the classical and mannose-binding lectin complement pathways in the events following skeletal muscle ischemia-reperfusion. J Immunol 177(11):8080-5. [PubMed: 17114482]  [MGI Ref ID J:140685]

Gadjeva M; Paludan SR; Thiel S; Slavov V; Ruseva M; Eriksson K; Lowhagen GB; Shi L; Takahashi K; Ezekowitz A; Jensenius JC. 2004. Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol 138(2):304-11. [PubMed: 15498041]  [MGI Ref ID J:106352]

Hart ML; Ceonzo KA; Shaffer LA; Takahashi K; Rother RP; Reenstra WR; Buras JA; Stahl GL. 2005. Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 174(10):6373-80. [PubMed: 15879138]  [MGI Ref ID J:99044]

Held K; Thiel S; Loos M; Petry F. 2008. Increased susceptibility of complement factor B/C2 double knockout mice and mannan-binding lectin knockout mice to systemic infection with Candida albicans. Mol Immunol 45(15):3934-41. [PubMed: 18672286]  [MGI Ref ID J:140046]

Hogaboam CM; Takahashi K; Ezekowitz RA; Kunkel SL; Schuh JM. 2004. Mannose-binding lectin deficiency alters the development of fungal asthma: effects on airway response, inflammation, and cytokine profile. J Leukoc Biol 75(5):805-14. [PubMed: 14761934]  [MGI Ref ID J:89442]

Ip WK; Takahashi K; Moore KJ; Stuart LM; Ezekowitz RA. 2008. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. J Exp Med 205(1):169-81. [PubMed: 18180310]  [MGI Ref ID J:131122]

Moller-Kristensen M; Hamblin MR; Thiel S; Jensenius JC; Takahashi K. 2007. Burn injury reveals altered phenotype in mannan-binding lectin-deficient mice. J Invest Dermatol 127(6):1524-31. [PubMed: 17363917]  [MGI Ref ID J:121549]

Moller-Kristensen M; Ip WK; Shi L; Gowda LD; Hamblin MR; Thiel S; Jensenius JC; Ezekowitz RA; Takahashi K. 2006. Deficiency of mannose-binding lectin greatly increases susceptibility to postburn infection with Pseudomonas aeruginosa. J Immunol 176(3):1769-75. [PubMed: 16424207]  [MGI Ref ID J:106353]

Moller-Kristensen M; Wang W; Ruseva M; Thiel S; Nielsen S; Takahashi K; Shi L; Ezekowitz A; Jensenius JC; Gadjeva M. 2005. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol 61(5):426-34. [PubMed: 15882434]  [MGI Ref ID J:106351]

Nimmerjahn F; Anthony RM; Ravetch JV. 2007. Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity. Proc Natl Acad Sci U S A 104(20):8433-7. [PubMed: 17485663]  [MGI Ref ID J:121840]

Petry F; Jakobi V; Wagner S; Tessema TS; Thiel S; Loos M. 2008. Binding and activation of human and mouse complement by Cryptosporidium parvum (Apicomplexa) and susceptibility of C1q- and MBL-deficient mice to infection. Mol Immunol 45(12):3392-400. [PubMed: 18501966]  [MGI Ref ID J:137680]

Stuart LM; Takahashi K; Shi L; Savill J; Ezekowitz RA. 2005. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol 174(6):3220-6. [PubMed: 15749852]  [MGI Ref ID J:97686]

Takahashi K; Gordon J; Liu H; Sastry KN; Epstein JE; Motwani M; Laursen I; Thiel S; Jensenius JC; Carroll M; Ezekowitz RA. 2002. Lack of mannose-binding lectin-A enhances survival in a mouse model of acute septic peritonitis. Microbes Infect 4(8):773-84. [PubMed: 12270724]  [MGI Ref ID J:90437]

Takahashi K; Shi L; Gowda LD; Ezekowitz RA. 2005. Relative roles of complement factor 3 and mannose-binding lectin in host defense against infection. Infect Immun 73(12):8188-93. [PubMed: 16299314]  [MGI Ref ID J:104305]

Walsh MC; Bourcier T; Takahashi K; Shi L; Busche MN; Rother RP; Solomon SD; Ezekowitz RA; Stahl GL. 2005. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol 175(1):541-6. [PubMed: 15972690]  [MGI Ref ID J:100604]

Zhang M; Takahashi K; Alicot EM; Vorup-Jensen T; Kessler B; Thiel S; Jensenius JC; Ezekowitz RA; Moore FD; Carroll MC. 2006. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J Immunol 177(7):4727-34. [PubMed: 16982912]  [MGI Ref ID J:139312]

Mbl2^tm1Kata related

Busche MN; Walsh MC; McMullen ME; Guikema BJ; Stahl GL. 2008. Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes. Diabetologia 51(8):1544-51. [PubMed: 18493734]  [MGI Ref ID J:137894]

Chan RK; Ibrahim SI; Takahashi K; Kwon E; McCormack M; Ezekowitz A; Carroll MC; Moore FD Jr; Austen WG Jr. 2006. The differing roles of the classical and mannose-binding lectin complement pathways in the events following skeletal muscle ischemia-reperfusion. J Immunol 177(11):8080-5. [PubMed: 17114482]  [MGI Ref ID J:140685]

Gadjeva M; Paludan SR; Thiel S; Slavov V; Ruseva M; Eriksson K; Lowhagen GB; Shi L; Takahashi K; Ezekowitz A; Jensenius JC. 2004. Mannan-binding lectin modulates the response to HSV-2 infection. Clin Exp Immunol 138(2):304-11. [PubMed: 15498041]  [MGI Ref ID J:106352]

Hart ML; Ceonzo KA; Shaffer LA; Takahashi K; Rother RP; Reenstra WR; Buras JA; Stahl GL. 2005. Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 174(10):6373-80. [PubMed: 15879138]  [MGI Ref ID J:99044]

Held K; Thiel S; Loos M; Petry F. 2008. Increased susceptibility of complement factor B/C2 double knockout mice and mannan-binding lectin knockout mice to systemic infection with Candida albicans. Mol Immunol 45(15):3934-41. [PubMed: 18672286]  [MGI Ref ID J:140046]

Ip WK; Takahashi K; Moore KJ; Stuart LM; Ezekowitz RA. 2008. Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. J Exp Med 205(1):169-81. [PubMed: 18180310]  [MGI Ref ID J:131122]

Moller-Kristensen M; Hamblin MR; Thiel S; Jensenius JC; Takahashi K. 2007. Burn injury reveals altered phenotype in mannan-binding lectin-deficient mice. J Invest Dermatol 127(6):1524-31. [PubMed: 17363917]  [MGI Ref ID J:121549]

Moller-Kristensen M; Ip WK; Shi L; Gowda LD; Hamblin MR; Thiel S; Jensenius JC; Ezekowitz RA; Takahashi K. 2006. Deficiency of mannose-binding lectin greatly increases susceptibility to postburn infection with Pseudomonas aeruginosa. J Immunol 176(3):1769-75. [PubMed: 16424207]  [MGI Ref ID J:106353]

Moller-Kristensen M; Wang W; Ruseva M; Thiel S; Nielsen S; Takahashi K; Shi L; Ezekowitz A; Jensenius JC; Gadjeva M. 2005. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol 61(5):426-34. [PubMed: 15882434]  [MGI Ref ID J:106351]

Petry F; Jakobi V; Wagner S; Tessema TS; Thiel S; Loos M. 2008. Binding and activation of human and mouse complement by Cryptosporidium parvum (Apicomplexa) and susceptibility of C1q- and MBL-deficient mice to infection. Mol Immunol 45(12):3392-400. [PubMed: 18501966]  [MGI Ref ID J:137680]

Stuart LM; Takahashi K; Shi L; Savill J; Ezekowitz RA. 2005. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype. J Immunol 174(6):3220-6. [PubMed: 15749852]  [MGI Ref ID J:97686]

Takahashi K; Shi L; Gowda LD; Ezekowitz RA. 2005. Relative roles of complement factor 3 and mannose-binding lectin in host defense against infection. Infect Immun 73(12):8188-93. [PubMed: 16299314]  [MGI Ref ID J:104305]

Walsh MC; Bourcier T; Takahashi K; Shi L; Busche MN; Rother RP; Solomon SD; Ezekowitz RA; Stahl GL. 2005. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury. J Immunol 175(1):541-6. [PubMed: 15972690]  [MGI Ref ID J:100604]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes at both loci.
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	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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Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

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.