Suppression of murine thyroiditis via blockade of the CD40–CD40L interaction

Carayanniotis, George; Masters, Sally R.; Noelle, Randolph J.

doi:10.1111/j.1365-2567.1997.00421.x

Cited by 93 publications

(67 citation statements)

References 43 publications

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“…2), both of which have been previously demonstrated to be directly or indirectly involved in induction of EAMG (31)(32)(33)(34)(35). The selective suppressive effect on Th1-type differentiation by anti-CD40L treatment is consistent with models of other autoimmune diseases such as multiple sclerosis, diabetes, and thyroiditis (17,18,36,37), and with graft-vshost disease and graft rejection (38,39).…”

Section: Figure 3 Effect Of Anti-cd40l Treatment On Costimulatory Fasupporting

confidence: 61%

“…CD40-CD40L interactions were previously found to be essential for the development of several autoimmune diseases including collagen-induced arthritis (11), autoimmune oophoritis (12), experimental allergic encephalomyelitis (EAE) (13,14), lupus nephritis (15,16), experimental autoimmune thyroiditis (17), and spontaneous autoimmune diabetes (18).…”

Section: Blockade Of Cd40 Ligand Suppresses Chronic Experimental Myasmentioning

confidence: 99%

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Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

Barchan

Maiti

et al. 2001

The Journal of Immunology

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Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-dependent Ab-mediated autoimmune disorders, in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. Th1-type cells and costimulatory factors such as CD40 ligand (CD40L) contribute to disease pathogenesis by producing proinflammatory cytokines and by activating autoreactive B cells. In this study we demonstrate the capacity of CD40L blockade to modulate EAMG, and analyze the mechanism underlying this disease suppression. Anti-CD40L Abs given to rats at the chronic stage of EAMG suppress the clinical progression of the autoimmune process and lead to a decrease in the AChR-specific humoral response and delayed-type hypersensitivity. The cytokine profile of treated rats suggests that the underlying mechanism involves down-regulation of AChR-specific Th1-regulated responses with no significant effect on Th2- and Th3-regulated AChR-specific responses. EAMG suppression is also accompanied by a significant up-regulation of CTLA-4, whereas a series of costimulatory factors remain unchanged. Adoptive transfer of splenocytes from anti-CD40L-treated rats does not protect recipient rats against subsequently induced EAMG. Thus it seems that the suppressed progression of chronic EAMG by anti-CD40L treatment does not induce a switch from Th1 to Th2/Th3 regulation of the AChR-specific immune response and does not induce generation of regulatory cells. The ability of anti-CD40L treatment to suppress ongoing chronic EAMG suggests that blockade of CD40L may serve as a potential approach for the immunotherapy of MG and other Ab-mediated autoimmune diseases.

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Section: Figure 3 Effect Of Anti-cd40l Treatment On Costimulatory Fasupporting

confidence: 61%

Section: Blockade Of Cd40 Ligand Suppresses Chronic Experimental Myasmentioning

confidence: 99%

Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

Barchan

Maiti

et al. 2001

The Journal of Immunology

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“…It is also effective in the treatment of a myriad of other autoimmune disease models, such as oophoritis (17), experimental autoimmune thyroiditis (18), lupus nephritis (19), collagen-induced arthritis (20), spontaneous autoimmune diabetes (21), and atherogenesis in hyperlipidemic mice (22). Based largely on in vitro experiments, it is thought that blockade of CD40 ligation prevents Th1 skewing (23,24).…”

Section: R Elapsing Experimental Autoimmune Encephalomyelitis (R-eae)mentioning

confidence: 99%

Autoimmune Intervention by CD154 Blockade Prevents T Cell Retention and Effector Function in the Target Organ

Howard

Miller

2001

The Journal of Immunology

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The CD40-CD154 interaction is an attractive target for therapeutic intervention in many autoimmune disorders, including multiple sclerosis. Previously, we showed that CD154 blockade both inhibited the onset of experimental autoimmune encephalomyelitis and blocked clinical disease progression (relapses) in mice with established disease. The mechanism of this protection is poorly understood. Because CD154 plays a role in Th1 development, its blockade has been thought to promote anti-inflammatory Th2 responses. However, these conclusions have primarily been based on extrapolated data from in vitro experiments, which may not accurately reflect the more complex events occurring in vivo. In this paper we determine how the immune response develops under the influence of therapeutic CD154 blockade in vivo. We demonstrate that anti-CD154 treatment does not alter the early expansion of Ag-specific T cells in secondary lymphoid organs or result in deviation to a Th2-dominant response. Interestingly, the late expansion and retention of Th1 cells in the lymph nodes were markedly reduced following immunization of Ab-treated mice, and this coincided with a recompartmentalization of these cells to the spleen. Most importantly, anti-CD154 treatment eliminated the retention/expansion of encephalitogenic Th1 cells, but not their entry into the CNS. These data indicate that a major mechanism by which CD154 blockade protects against autoimmune disease is by controlling the amplitude of acute phase Th1 responses in the draining lymph nodes and by preventing the sustained expansion of effector cells within the target organ.

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“…The prevention of disease development has been demonstrated in a variety of animal models, including graft versus host disease (31), experimental allergic encephalomyelitis (32), collagen-induced arthritis (33), and autoimmune thyroiditis (34), when animals are treated with inhibitory anti-CD154 antibodies at the onset or in the early stages of disease initiation. Blockade of the CD40/CD154 signal has been demonstrated to decrease inflammation in models of antibody-mediated membranous GN when animals are treated in the early stages of disease development (35) and in murine models of autoimmune lupus nephritis (36,37).…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Renal Cell Expression of CD40 Directs Th1 Effectors Inducing Experimental Crescentic Glomerulonephritis

Ruth

Kitching

Semple

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Evidence suggests that human and experimental crescentic GN results from Th1-predominant immunity to glomerular antigens. CD40/CD154 signaling plays a key role in initiating Th1 responses and may direct Th1 effector responses. The role of CD40 in the development of GN was assessed in murine experimental anti-glomerular basement membrane GN. In this model, C57BL/6 wild-type (WT) mice sensitized to sheep globulin develop crescentic GN resulting from Th1 effector responses when challenged with sheep globulin planted in glomeruli. CD40Ϫ/Ϫ mice do not develop immunity in response to sheep globulin and thus fail to develop effector responses or significant GN. CD40 is expressed in nephritic glomeruli, suggesting a potential role for intrarenal CD40-CD154 interactions in injurious effector responses. Immune neutralization of the CD40 ligand (CD154) at the time of challenge significantly reduced accumulation of Th1 effectors and injury. The role of CD40 expression by renal cells was assessed by comparing GN in WT3 CD40Ϫ/Ϫ chimeras (absent renal but intact bone marrow CD40) and sham chimeric mice (WT3 WT). Both groups developed strong antigen-specific immune responses (antibody and IFN-␥ production). However, WT3 CD40Ϫ/Ϫ chimeras demonstrated reduced renal monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA levels and minimal T cell and macrophage influx and were protected from renal injury. Sham chimeric mice developed reduced GFR, with prominent renal expression of monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA and effector cell accumulation. In conclusion, the expression of CD40 by nonimmune renal cells plays a major role in Th1 effector responses by inducing Th1 chemokine production. Therefore, CD40-CD154 interactions are a potential therapeutic target in GN.Cell-cell interactions play a vital role in mediating adaptive immune responses. Two types of signals have been defined as being required for the initiation of T cell-dependent immune responses (1). The first type is the T cell receptor/MHCmediated signal and the second type results from the binding of costimulatory/accessory receptor ligand pairs, which bidirectionally deliver signals to the T cells and antigen-presenting cells to confer functional activity (2). CD40/CD154 is one such costimulatory pair whose regulatory role in the initiation of adaptive immune responses has been clearly defined (3). The importance of CD40/CD154 signaling in the mediation of effector responses has also been highlighted. The CD40 signal has been demonstrated to be required for delivery of optimal functional capacity to macrophages, with increases in the production of IL-12, IL-8, and IL-1 (4,5). Ligation of CD40 expressed by macrophages leads to upregulation of intercellular adhesion molecule-1, MHC class II, and B7-2 (6). CD40-dependent activation of endothelial cells leads to upregulation of adhesion molecules, facilitating leukocyte migration to inflammatory sites (7,8). The CD40 signal enhances effector functions in concert with the pr...

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Suppression of murine thyroiditis via blockade of the CD40–CD40L interaction

Cited by 93 publications

References 43 publications

Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

Blockade of CD40 Ligand Suppresses Chronic Experimental Myasthenia Gravis by Down-Regulation of Th1 Differentiation and Up-Regulation of CTLA-4

Autoimmune Intervention by CD154 Blockade Prevents T Cell Retention and Effector Function in the Target Organ

Intrinsic Renal Cell Expression of CD40 Directs Th1 Effectors Inducing Experimental Crescentic Glomerulonephritis

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