Vaccination Route That Induces Transforming Growth Factor β Production Fails To Elicit Protective Immunity against Leishmania donovani Infection

ABSTRACT BALB/c mice immunized intraperitoneally (i.p.) and intravenously (i.v.) with Leishmania donovani promastigote membrane antigens (LAg), either free or encapsulated in liposomes, were protected against challenge infection with L. donovani, whereas mice immunized by the subcutaneous (s.c.) and intramuscular routes were not protected. Protected mice showed strong parasite resistance in both the liver and spleen, along with enhanced immunoglobulin G2a and delayed-type hypersensitivity responses. Again, mice vaccinated through the i.p. and i.v. routes showed high levels of NO production after challenge infection. s.c. vaccination resulted in an increased capacity of the spleen cells to produce prechallenge transforming growth factor β (TGF-β) levels during the in vitro antigen recall response, whereas i.p. immunization induced production of prechallenge gamma interferon, interleukin-12 (IL-12), and IL-4 levels, with a Th1 bias. Exposure to antigen-stimulated splenocyte supernatants of i.p. but not s.c. immunized mice activated macrophages for in vitro parasite killing. As an enhanced level of TGF-β was detected in supernatants from unprotected s.c. immunized mice, neutralization by anti-TGF-β antibody enhanced in vitro macrophage killing activity. The suppressive role of this cytokine was evaluated in vivo by vaccination with liposomal LAg and anti-TGF-β antibody. Upon parasite challenge, these animals showed significant protection in both the liver and spleen. Moreover, the addition of recombinant TGF-β in splenocyte supernatants of i.p. immunized mice in vitro as well as in vivo inhibited the protective ability of the macrophages by the i.p. route. Thus, the induction of high prechallenge TGF-β limits the efficacy of vaccination by routes that are nonprotective.

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Transforming Growth Factor β and Immunosuppression in Experimental Visceral Leishmaniasis

Infection and Immunity ◽

10.1128/iai.66.3.1233-1236.1998 ◽

1998 ◽

Vol 66 (3) ◽

pp. 1233-1236 ◽

Cited By ~ 48

Author(s):

Virmondes Rodrigues ◽

João Santana da Silva ◽

Antonio Campos-Neto

Keyword(s):

T Cells ◽

Growth Factor ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Spleen Cells ◽

Immunohistochemical Studies

ABSTRACT Hamsters infected with Leishmania donovani develop a disease similar to human kala-azar. They present hypergammaglobulinemia, and their T cells do not respond to parasite antigens. This unresponsiveness has been primarily ascribed to defects in antigen-presenting cells (APCs), because these cells are unable to stimulate proliferation of parasite-specific T cells from immunized animals. In this study, we show that APCs (adherent spleen cells) fromL. donovani-infected hamsters produce high levels of the inhibitory cytokine transforming growth factor β (TGF-β). Immunohistochemical studies with an anti-TGF-β monoclonal antibody (MAb) showed that this cytokine is abundantly produced in vivo by the spleen cells of infected animals. In addition, high levels of TGF-β are produced in vitro by infected hamster cells, either spontaneously or after stimulation with parasite antigen or lipopolysaccharide. Furthermore, in vivo-infected adherent cells obtained from spleens ofL. donovani-infected hamsters caused profound inhibition of the in vitro antigen-induced proliferative response of lymph node cells from hamsters immunized with leishmanial antigens. Moreover, this inhibition was totally abrogated by the anti-TGF-β MAb. These results suggest that the immunosuppression observed in visceral leishmaniasis is, at least in part, due to the abundant production of TGF-β during the course of the infection.

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Targeting Transforming Growth Factor-β in Metastasis: In Vitro and In Vivo Mechanisms

Transforming Growth Factor-β in Cancer Therapy, Volume II ◽

10.1007/978-1-59745-293-9_37 ◽

2008 ◽

pp. 609-634 ◽

Cited By ~ 1

Author(s):

Michael Reiss

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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Estrogen Protects Lenses against Cataract Induced by Transforming Growth Factor-β (TGFβ)

Journal of Experimental Medicine ◽

10.1084/jem.185.2.273 ◽

1997 ◽

Vol 185 (2) ◽

pp. 273-280 ◽

Cited By ~ 71

Author(s):

Angela M. Hales ◽

Coral G. Chamberlain ◽

Christopher R. Murphy ◽

John W. McAvoy

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Hormone Replacement ◽

Transforming Growth Factor Β ◽

Epidemiological Studies ◽

Female Rats ◽

World Population ◽

Damaging Effects

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-β (TGFβ) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFβ-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFβ and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFβ. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.

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Selective in vivo antagonism of endothelin receptors in transforming growth factor-β1 transgenic mice that mimic the vascular pathology of Alzheimer’s diseaseThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-042 ◽

2010 ◽

Vol 88 (6) ◽

pp. 652-660 ◽

Cited By ~ 13

Author(s):

Panayiota Papadopoulos ◽

Brice Ongali ◽

Edith Hamel

Keyword(s):

Growth Factor ◽

Transgenic Mice ◽

Cognitive Deficit ◽

Transforming Growth Factor ◽

Memory Performance ◽

Transforming Growth Factor Β ◽

Cerebrovascular Reactivity ◽

Vascular Pathology ◽

No Production

Increased levels of transforming growth factor-β1(TGF-β1) induce a vascular pathology that shares similarities with that seen in Alzheimer’s disease, and which possibly contributes to the cognitive decline. In aged transgenic mice that overexpress TGF-β1(TGF mice), we previously found reduced dilatory function and selectively impaired endothelin-1 (ET-1)-induced contraction. Here we studied the effects of chronic treatments with selective ETA(ABT-627) or ETB(A-192621) receptor antagonist on cerebrovascular reactivity, cerebral perfusion, or memory performance. The dilatory deficit of TGF mice was not improved by either treatment, but both ET-1 contraction and basal nitric oxide (NO) production were distinctly altered. Although ABT-627 was devoid of any effect in TGF mice, it virtually abolished the ET-1-induced contraction and NO release in wild-type (WT) littermates. In contrast, A-192621 only acted upon TGF mice with full recovery of ET-1 contraction and baseline NO synthesis. TGF mice, treated or not, had no cognitive deficit in the Morris water maze, nor did ABT-627-treated WT controls despite severely impaired vasoreactivity. These findings confirm that ETAreceptors primarily mediate the ET-1-induced contraction. Further, they suggest that ETBreceptors play a detrimental role in conditions of increased TGF-β1and that vascular dysfunction does not inevitably lead to cognitive deficit.

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