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Mouse Invariant Monoclonal Antibody NKT14: A Novel Tool to Manipulate iNKT Cell Function In Vivo.

Scheuplein F, Lamont DJ, Poynter ME, Boyson JE, Serreze D, Lundblad LK, Mashal R, Schaub R - PLoS ONE (2015)

Bottom Line: Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery.This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth.These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.

View Article: PubMed Central - PubMed

Affiliation: NKT Therapeutics, Inc., Waltham, MA, United States of America.

ABSTRACT
Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.

No MeSH data available.


Related in: MedlinePlus

Starting at 4 week of age female NOD mice were injected i.p. every 6 weeks with the isotype control, NKT14, or NKT14m antibodies.Animals were monitored weekly for glycosuria. Positive animals (>300 mg/dL Glucose) were tested again the next day and euthanized if positive.
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pone.0140729.g003: Starting at 4 week of age female NOD mice were injected i.p. every 6 weeks with the isotype control, NKT14, or NKT14m antibodies.Animals were monitored weekly for glycosuria. Positive animals (>300 mg/dL Glucose) were tested again the next day and euthanized if positive.

Mentions: It has been reported that the absence or activation of iNKT cells respectively accelerates and retards T1D onset in NOD mice [11,13]. Starting at four weeks of age NOD mice were treated at 6 week intervals with isotype control (n = 20), NKT14 (n = 10), or NKT14m (n = 20) antibodies and monitored weekly for the inset of glycosuria. As predicted from the studies employing genetic ablation of CD1d expression, or the aGalCer iNKT agonist, NKT14 mediated depletion of iNKT cells led to significantly accelerated onset of T1D in NOD mice (P>0.01 Log-Rank (Mantel-Cox)), while their activation mediated by repeated administration of the NKT14m antibody partially protected and significantly delayed disease onset (P<0.05 Log Rank Mantel-Cox) (Fig 3).


Mouse Invariant Monoclonal Antibody NKT14: A Novel Tool to Manipulate iNKT Cell Function In Vivo.

Scheuplein F, Lamont DJ, Poynter ME, Boyson JE, Serreze D, Lundblad LK, Mashal R, Schaub R - PLoS ONE (2015)

Starting at 4 week of age female NOD mice were injected i.p. every 6 weeks with the isotype control, NKT14, or NKT14m antibodies.Animals were monitored weekly for glycosuria. Positive animals (>300 mg/dL Glucose) were tested again the next day and euthanized if positive.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608835&req=5

pone.0140729.g003: Starting at 4 week of age female NOD mice were injected i.p. every 6 weeks with the isotype control, NKT14, or NKT14m antibodies.Animals were monitored weekly for glycosuria. Positive animals (>300 mg/dL Glucose) were tested again the next day and euthanized if positive.
Mentions: It has been reported that the absence or activation of iNKT cells respectively accelerates and retards T1D onset in NOD mice [11,13]. Starting at four weeks of age NOD mice were treated at 6 week intervals with isotype control (n = 20), NKT14 (n = 10), or NKT14m (n = 20) antibodies and monitored weekly for the inset of glycosuria. As predicted from the studies employing genetic ablation of CD1d expression, or the aGalCer iNKT agonist, NKT14 mediated depletion of iNKT cells led to significantly accelerated onset of T1D in NOD mice (P>0.01 Log-Rank (Mantel-Cox)), while their activation mediated by repeated administration of the NKT14m antibody partially protected and significantly delayed disease onset (P<0.05 Log Rank Mantel-Cox) (Fig 3).

Bottom Line: Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery.This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth.These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.

View Article: PubMed Central - PubMed

Affiliation: NKT Therapeutics, Inc., Waltham, MA, United States of America.

ABSTRACT
Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.

No MeSH data available.


Related in: MedlinePlus