The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.

K Kishimoto; V M Dong; Shohreh Issazadeh-Navikas; E V Fedoseyeva; A M Waaga; A Yamada; M Sho; G Benichou; H Auchincloss; M J Grusby; S J Khoury; M H Sayegh

doi:10.1172/JCI9586

The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.

K Kishimoto, V M Dong, Shohreh Issazadeh-Navikas, E V Fedoseyeva, A M Waaga, A Yamada, M Sho, G Benichou, H Auchincloss, M J Grusby, S J Khoury, M H Sayegh

118 Citations (Scopus)

Abstract

We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.

Original language	English
Journal	Journal of Clinical Investigation
Volume	106
Issue number	1
Pages (from-to)	63-72
Number of pages	9
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI9586
Publication status	Published - 2000

Access to Document

10.1172/JCI9586

Cite this

Kishimoto, K., Dong, V. M., Issazadeh-Navikas, S., Fedoseyeva, E. V., Waaga, A. M., Yamada, A., Sho, M., Benichou, G., Auchincloss, H., Grusby, M. J., Khoury, S. J., & Sayegh, M. H. (2000). The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo. Journal of Clinical Investigation, 106(1), 63-72. https://doi.org/10.1172/JCI9586

Kishimoto, K, Dong, VM, Issazadeh-Navikas, S, Fedoseyeva, EV, Waaga, AM, Yamada, A, Sho, M, Benichou, G, Auchincloss, H, Grusby, MJ, Khoury, SJ & Sayegh, MH 2000, 'The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.', Journal of Clinical Investigation, vol. 106, no. 1, pp. 63-72. https://doi.org/10.1172/JCI9586

@article{0acc827057cd11dd8d9f000ea68e967b,

title = "The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.",

abstract = "We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.",

author = "K Kishimoto and Dong, {V M} and Shohreh Issazadeh-Navikas and Fedoseyeva, {E V} and Waaga, {A M} and A Yamada and M Sho and G Benichou and H Auchincloss and Grusby, {M J} and Khoury, {S J} and Sayegh, {M H}",

note = "Keywords: Animals; Antigens, CD28; Antigens, CD40; Antigens, CD80; CD40 Ligand; Cytokines; DNA-Binding Proteins; Graft Rejection; Heart Transplantation; Membrane Glycoproteins; Mice; Mice, Inbred Strains; STAT4 Transcription Factor; STAT6 Transcription Factor; Th1 Cells; Th2 Cells; Trans-Activators; Transplantation, Homologous",

year = "2000",

doi = "10.1172/JCI9586",

language = "English",

volume = "106",

pages = "63--72",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "1",

}

TY - JOUR

T1 - The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.

AU - Kishimoto, K

AU - Dong, V M

AU - Issazadeh-Navikas, Shohreh

AU - Fedoseyeva, E V

AU - Waaga, A M

AU - Yamada, A

AU - Sho, M

AU - Benichou, G

AU - Auchincloss, H

AU - Grusby, M J

AU - Khoury, S J

AU - Sayegh, M H

N1 - Keywords: Animals; Antigens, CD28; Antigens, CD40; Antigens, CD80; CD40 Ligand; Cytokines; DNA-Binding Proteins; Graft Rejection; Heart Transplantation; Membrane Glycoproteins; Mice; Mice, Inbred Strains; STAT4 Transcription Factor; STAT6 Transcription Factor; Th1 Cells; Th2 Cells; Trans-Activators; Transplantation, Homologous

PY - 2000

Y1 - 2000

N2 - We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.

AB - We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans.

U2 - 10.1172/JCI9586

DO - 10.1172/JCI9586

M3 - Journal article

C2 - 10880049

SN - 0021-9738

VL - 106

SP - 63

EP - 72

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

ER -

The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo.

Abstract

Access to Document

Fingerprint

Cite this