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Research ArticleInflammation, Immunopharmacology, and Asthma

Cannabidiol Enhances Intestinal Cannabinoid Receptor Type 2 Receptor Expression and Activation Increasing Regulatory T Cells and Reduces Murine Acute Graft-versus-Host Disease without Interfering with the Graft-versus-Leukemia Response

Bárbara Betônico Berg, Jaqueline Silva Soares, Isabela Ribeiro Paiva, Barbara Maximino Rezende, Milene Alvarenga Rachid, Stêfany Bruno de Assis Cau, Thiago Roberto Lima Romero, Vanessa Pinho, Mauro Martins Teixeira and Marina Gomes Miranda e Castor
Journal of Pharmacology and Experimental Therapeutics May 2021, 377 (2) 273-283; DOI: https://doi.org/10.1124/jpet.120.000479
Bárbara Betônico Berg
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Jaqueline Silva Soares
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Isabela Ribeiro Paiva
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Barbara Maximino Rezende
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Milene Alvarenga Rachid
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Stêfany Bruno de Assis Cau
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Thiago Roberto Lima Romero
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Vanessa Pinho
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Mauro Martins Teixeira
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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Marina Gomes Miranda e Castor
Departamento de Farmacologia-ICB/UFMG (B.B.B., J.S.S., I.R.P., S.B.d.A.C., T.R.L.R., M.G.M.e.C.); Programa de Pós-graduação em Fisiologia e Farmacologia da UFMG (B.B.B., I.R.P., S.B.d.A.C., T.R.L.R., M.M.T., M.G.M.e.C.); Departamento de Enfermagem Básica da Escola de Enfermagem da UFMG (B.M.R.); Departamento de Patologia Geral do Instituto de Ciências Biológicas da UFMG (M.A.R.); Departamento de Morfologia - CPDF-ICB/UFMG (V.P.); and Departamento de Bioquímica e Imunologia, CPDF-ICB/UFMG (M.M.T.), Belo Horizonte, Brazil
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    Fig. 1.

    Clinical aspects of experimental aGVHD. (A) Allogeneic transplant was performed from C57BL6j mice with H2Db phenotype to Balb-c mice with H2Dd phenotype. (B) Mice were treated with CBD 10 mg/kg, CBD 30 mg/kg, CBD 60 mg/kg, or vehicle, and their survival was assessed daily. (C) Daily assessment of mice through clinical score. (D) Bone marrow engraftment was verified in vehicle and CBD 30 mg/kg 7 days after the transplant through flow cytometry. * indicates P < 0.05 when compared with control group and # indicates P < 0.05 when compared with the vehicle. Data are expressed in dispersion with mean, and statistical difference was determined by Student’s t test for engraftment and log-rank (Mantel-Cox) test for survival. n = 5 for all groups

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    Fig. 2.

    Flow cytometry of mice spleen 7 days after disease induction. (A) Total lymphocytes; (B) CD3+CD4+ cells; (C) CD3+CD8+ cells; (D) CD3+CD4+CD28+; (E) CD3+CD8+CD28+; and (F) CD4+CD25+FoxP3+. * indicates P < 0.05 when compared with control group and # when P < 0.05 when compared with vehicle. Data are expressed in dispersion with mean, and statistical difference was determined by ANOVA with Fisher’s LSD post hoc. n = 5 for all groups

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    Fig. 3.

    Intestines stained with H&E, (A) control, (B) vehicle, and (C) CBD; stars represent edema, the dashed circle represents intestinal crypt, and arrows point to mononuclear infiltrate. (D) Quantification of the histopathological score; the preservation of the intestine morphology is translated in (E) reduced bacteria translocation. Data are expressed in dispersion with mean, and statistical difference was determined by ANOVA with Fisher’s LSD post hoc; n = 5 for all groups.

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    Fig. 4.

    Flow cytometry and ELISA of mice small intestines 7 days after disease induction. (A) Total lymphocytes; (B) CD3+CD4+ cells n = 5/5/5; (C) CD3+CD8+ cells n = 5/5/5; (D) CD3+CD4+CD28+ n = 5/5/4; (E) CD3+CD8+CD28+ n = 5/5/4; (F) CD4+CD25+FoxP3+ n = 5/5/5 cells; (G) CCL2, (H) CCL3, (I) CCL5, (J) TNFα, (K) IFNγ, and (L) IL-10. Data are represented in dispersion graphs with mean; n = 5 for all groups, except when specified. * indicates P < 0.05 when compared with control group and # when P < 0.05 when compared with vehicle. Data are expressed in dispersion with mean, and statistical difference was determined by ANOVA with Fisher’s LSD post hoc.

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    Fig. 5.

    Liver analysis. H&E from groups (A) control, (B) vehicle, and (C) CBD; dark arrows represent mononuclear infiltrate. (D) Quantification of histopathological score; ELISA of (E) CCL2, (F) CCL3, (G) CCL5, (H) TNFα, (I) IFNγ, and (J) IL-10; flow cytometry displaying (K) total lymphocytes; (L) CD3+CD4+ cells; (M) CD3+CD8+ cells; (N) CD3+CD4+CD28+ cells; (O) CD3+CD8+CD28+ cells; and (P) CD4+CD25+FoxP3+ cells. * indicates P < 0.05 when compared with control group and # when P < 0.05 when compared with vehicle. Data are expressed in dispersion with mean, and statistical difference was determined by ANOVA with Fisher’s LSD post hoc; n = 5 for all groups.

  • Fig. 6.
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    Fig. 6.

    Flow cytometry of mice spleen and lymph nodes (LNs) 7 days after disease induction and P815GFP+ cells transplant. (A) Percentage of P815+ cells in lymph nodes. (B) Percentage of P815+ cells in spleen. Absolute number of P815+ cells are represented in dispersion graphs next to flow-cytometry shards; n = 5 for all groups.

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    Fig. 7.

    Role of CB2 in the protective effect of CBD. (A) CBD in the presence of CB1 antagonist; (B) CBD in the presence of CB2 antagonist; (C) treatment with CB1 antagonist without CBD; (D) treatment with CB2 antagonist without CBD. (E) CD4 and CB2 mean integrated density, colocalization of CD4/CB2, and representative figures of groups (CD4 FITC, CB2 AlexaFluor 594, and DAPI); (F) CD8 and CB2 mean integrated density, colocalization of CD8/CB2, and representative figures of groups (CD8 PerCP, CB2 AlexaFluor 488, and DAPI); (G) FoxP3 and CB2 mean integrated density, colocalization of FoxP3/CB2, and representative figures of groups (FoxP3, CB2 AlexaFluor 488, and DAPI). Differences between groups were assessed with log-rank (Mantel-Cox) test for P < 0.05; n = 10/10/5/5 for survival and ANOVA with Fisher’s LSD post hoc; n = 5 for all groups in immunofluorescence. ns, not significant.

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    Fig. 8.

    Schematic representation of our findings. CBD treatment, partially by CB2 receptor activation, increased the number of Tregs in the intestines and reduced cytokine/chemokine release. Together these factors led to the protection of target organs and the increase in mice survival.

Additional Files

  • Figures
  • Data Supplement

    • Supplemental Figures -

      Supplemental Figure 1. Antibodies used in immunofluorescence.

      Supplemental Figure 2. Flow cytometry analysis of spleen.

      Supplemental Figure 3. Flow cytometry analysis of small intestine.

      Supplemental Figure 4. Flow cytometry analysis of liver.

      Supplemental Figure 5. Immunofluorescence of CD4/CB2 in small intestine.

      Supplemental Figure 6. Immunofluorescence of FoxP3/CB2 in small intestine.

      Supplemental Figure 7. Immunofluorescence of CD8/CB2 in small intestine.

      Supplemental Figure 8. Intravital analysis after GVHD was induced in Balb/c mice using C57BL/6J GFP+ mice as donors.

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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleInflammation, Immunopharmacology, and Asthma

CBD Enhances Treg Cells and Reduces GVHD by CB2 Activation

Bárbara Betônico Berg, Jaqueline Silva Soares, Isabela Ribeiro Paiva, Barbara Maximino Rezende, Milene Alvarenga Rachid, Stêfany Bruno de Assis Cau, Thiago Roberto Lima Romero, Vanessa Pinho, Mauro Martins Teixeira and Marina Gomes Miranda e Castor
Journal of Pharmacology and Experimental Therapeutics May 1, 2021, 377 (2) 273-283; DOI: https://doi.org/10.1124/jpet.120.000479

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Research ArticleInflammation, Immunopharmacology, and Asthma

CBD Enhances Treg Cells and Reduces GVHD by CB2 Activation

Bárbara Betônico Berg, Jaqueline Silva Soares, Isabela Ribeiro Paiva, Barbara Maximino Rezende, Milene Alvarenga Rachid, Stêfany Bruno de Assis Cau, Thiago Roberto Lima Romero, Vanessa Pinho, Mauro Martins Teixeira and Marina Gomes Miranda e Castor
Journal of Pharmacology and Experimental Therapeutics May 1, 2021, 377 (2) 273-283; DOI: https://doi.org/10.1124/jpet.120.000479
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