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Andrea Cavani

Publications and source records attributed to Andrea Cavani.

11 recordsLinked to original sources
PubMed2006

CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation.

Psoriasis is an immune-mediated skin disease characterized by lymphocytic infiltration and altered keratinocyte differentiation. Using immunohistochemical techniques we found that the cellular infiltrate in acute psoriatic plaques includes 5-8% CD3(-)CD56(+) natural killer (NK) cells, mostly localized in the mid and papillary dermis. NK lymphocytes isolated from punch biopsy specimens of psoriatic plaques showed a CD56(bright)CD16(-)CD158b(-) phenotype, failed to express the skin homing cutaneous lymphocyte-associated antigen and released abundant IFN-gamma upon stimulation. Supernatants from psoriatic NK cells induced MHC class II and ICAM-1 expression and release of CXCL10 and CCL5 by cultured psoriatic keratinocytes. Skin NK cells expressed high levels of the chemokines receptors CXCR3 and CCR5, intermediate amounts of CXCR1, CCR6 and CCR8, and low levels of CCR1, CCR2, CCR4, CCR7 and CX3CR1. In addition, they promptly migrated in vitro toward CXCL10, CCL5, supernatants of IFN-gamma-activated psoriatic keratinocytes and, to a lower extent, CCL20 and CCL4. In contrast, they failed to migrate toward CXCL8, CCL1, CCL2, CCL3, CCL17, CCL19 and CX3CL1. Taken together, our results implicate NK lymphocytes as newly identified protagonists in the pathogenesis of psoriasis. Their distinctive homing properties should be taken into account in the design of specific therapy aimed at blocking pathogenic cell accumulation in the skin.

CD56 Antigen↗
PubMed2006

The role of T cells in drug reaction.

T cells are major protagonists of immune-mediated adverse drug eruptions. Immunohistochemical observation as well as isolation and functional characterization of T cells infiltrating the affected tissues provided new insights into the pathomechanisms of the diverse clinical manifestations of drug hypersensitivity, and permitted the recognition of T cell-mediated cytotoxicity against drug-loaded resident cells as a major mechanism of tissue damage.

CD4-Positive T-Lymphocytes↗
PubMed2005

Breaking tolerance to nickel.

Nickel is a ubiquitous metal frequently responsible of allergic skin reactions. Development of undesired reaction to nickel has been positively correlated with the expansion of specific CD8+ T cells, that induce apoptosis of nickel-loaded keratinocytes through a perforin-dependent mechanism. In non allergic individuals, the lack of circulating CD8+ T cells reactive to nickel, as well as the absence of inflammatory responses at the site of skin exposure to the metal are the consequence of the expansion of specialized T cells with regulatory function. Among these, CD4(+)CD25+ T cells from peripheral blood of non allergic subjects strongly regulate immune responses to nickel in a cytokine-independent, cell-contact-dependent mechanism. In contrast, CD4(+)CD25+ obtained from the blood of nickel-allergic individuals have limited or absent suppressive activity on specific T cell responses in vitro.

Animals↗
PubMed2004

Immunoregulation of allergic contact dermatitis.

Allergic contact dermatitis (ACD) to haptens can serve as a valuable paradigm for understanding the physiopathology of T cell mediated immune responses. In sensitized individuals, exposure to the relevant hapten initiates clinical expression of ACD, which depends on the rapid activation of specific T cells. Mechanisms of tissue damage include direct cytotoxicity against keratinocytes, mostly mediated by CD8+ T cells, and T cell release of cytokines, which amplify the inflammatory response by targeting resident skin cells. The expression of ACD is actively regulated by specialized subsets of T lymphocytes with suppressive functions. In particular, T regulatory cells producing high levels of IL-10 suppress ACD by blocking the functions of dendritic cells. In contrast CD4+CD25+ regulatory T cells prevent immunopathological reactions and maintain peripheral tolerance to haptens by acting via a cell-to-cell contact mechanism. Understanding the role of suppressor T cells and the requirements for their in vivo and in vitro expansion are critical steps for the development of specific desensitization protocols in hapten-allergic individuals. This information may also provide the basis for novel interventions in other immune-mediated diseases.

CD4-Positive T-Lymphocytes↗
PubMed2003

Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals.

We investigated the capacity of CD25(+) T regulatory cells (Treg) to modulate T cell responses to nickel, a common cause of allergic contact dermatitis. CD4(+) T cells isolated from the peripheral blood of six healthy, nonallergic individuals showed a limited capacity to proliferate in response to nickel in vitro, but responsiveness was strongly augmented (mean increment +/- SD, 240 +/- 60%) when cells were depleted of CD25(+) Treg. Although CD25(+) Treg were anergic to nickel, a small percentage up-regulated membrane CTLA-4 upon nickel exposure. CD25(+) Treg strongly and dose-dependently inhibited nickel-specific activation of CD25(-) T lymphocytes in coculture experiments in a cytokine-independent, but cell-to-cell contact-dependent, manner. Approximately 30% of circulating CD25(+) Treg expressed the cutaneous lymphocyte-associated Ag (CLA), and CLA(+)CD25(+) Treg were more efficient than CLA(-)CD25(+) cells in suppressing nickel responsiveness of CD25(-) T cells. The site of a negative patch test in response to nickel showed an infiltrate of CD4(+)CLA(+) cells and CD25(+) cells, which accounted for approximately 20% of the total T cells isolated from the tissue. Skin-derived T cells suppressed nickel-specific responses of peripheral blood CD25(-) T cells. In addition, 60 +/- 14% of peripheral blood CD25(+) Treg expressed the chemokine receptor CCR7 and strongly inhibited naive T cell activation in response to nickel. Finally, CD25(+) T cells isolated from peripheral blood of nickel-allergic patients showed a limited or absent capacity to suppress metal-specific CD4(+) and CD8(+) T cell responses. The results indicates that in healthy individuals CD25(+) Treg can control the activation of both naive and effector nickel-specific T cells.

Adult↗
PubMed2003

Immunoregulation of hapten and drug induced immune reactions.

PURPOSE OF REVIEW: Unbalanced immune responses to haptens lead to a variety of diseases, including allergic contact dermatitis to skin sensitizers and drug induced immune reactions. The occurrence, magnitude and persistence of immune responses are modulated by specialized T cell subsets with regulatory function. The purpose of this brief review is to summarize the recent data on the role of regulatory T cells in the control of hapten mediated diseases. RECENT FINDINGS: Several subsets of regulatory T cells, including T regulatory cell 1-like lymphocytes, and cutaneous lymphocyte associated antigen+ CD4+CD25+ regulatory T cells have been isolated from the skin at sites of hapten challenge. Both cell types suppress specific T cell responses to cutaneous sensitizers, such as nickel. SUMMARY: Although data concerning the regulation of drug hypersensitivity are lacking, several reports indicate the role of regulatory T cell subsets in allergic contact dermatitis to haptens. The understanding of their role in hapten diseases and the requirement for their in-vivo and in-vitro expansion appears as a critical step for the development of specific desensitization protocols.

Animals↗
PubMed2002

The role of chemokines in allergic contact dermatitis.

Chemokines are important mediators of immune-mediated skin diseases. Allergic contact dermatitis (ACD) is the most thoroughly investigated T cell-mediated disorder because of the ability to easily reproduce the lesions in humans and the availability of an excellent mouse model. Migration of dendritic cells from the skin to lymph nodes is absolutely required for induction of hapten sensitization, and depends upon expression of CCR7 by mature dendritic cells and SLC in the lymph nodes. During expression of ACD, recruitment of T lymphocytes is driven by chemokines exposed on the surface of endothelial cells or released by activated resident skin cells such as mast cells, fibroblasts and keratinocytes. Chemokines are produced in a coordinated and sequential manner, with IL-8 and RANTES induced by TNF-alpha during early stages, and MCP-1, IP-10, Mig, I-TAC, I-309 and MDC induced by IFN-gamma during later stages. Infiltrating monocytes, dendritic cells and T cells are additional sources of chemokines for further leukocyte accumulation. Distinct T cell subsets express different chemokine receptors, with type 2 cells mostly attracted by eotaxin, MDC, TARC and I-309, and type 1 cells sensitive to IP-10, Mig, I-TAC, RANTES and MIP-1beta. MCP-1 is effective on both subsets. T regulatory cells, which inhibit dendritic cell function and are probably involved in the termination of ACD, are sensitive to MCP-1, MIPs and TARC, but express high levels of CCR8 and are more specifically attracted by I-309. Targeting chemokines and chemokine receptors may offer new opportunities for therapeutic interventions in ACD and other chronic inflammatory skin diseases.

Animals↗
PubMed2002

Activation of nickel-specific CD4+ T lymphocytes in the absence of professional antigen-presenting cells.

Allergic contact dermatitis ensues from exaggerated T cell responses to haptens. Dendritic cells are required for the initiation of hapten sensitization, but they may not be necessary for disease expression. Here we investigated the antigen-presenting cell requirement of nickel-specific CD4+ lymphocytes isolated from the blood of six allergic individuals. A significant proportion (42 out of 121; 35%) of the T cell clones proliferated in vitro to nickel also in the absence of professional antigen-presenting cells, suggesting a direct T-T hapten presentation. Antigen-presenting-cell-independent T cells showed a predominant T helper 1 phenotype. Nickel recognition by these T cells was major histocompatibility complex class II restricted, not influenced by CD28 triggering, independent from their state of activation, and did not require processing. The capacity of this T cell subset to be directly stimulated by nickel was not due to unique antigen-presenting properties, as both antigen-presenting-cell-dependent and antigen-presenting-cell-independent clones displayed comparable levels of HLA-DR, CD80, and CD86, and were equally capable of presenting nickel to antigen-presenting-cell-independent clones. In contrast, neither T cell types activated antigen-presenting-cell-dependent T lymphocytes. T-T presentation induced T cell receptor downregulation, CD25, CD80, CD86, and HLA-DR upregulation, and interferon-gamma release, although to a lesser extent compared to those induced by dendritic cell-T presentation. Following T-T presentation, the clones did not undergo unresponsiveness and maintained the capacity to respond to dendritic cells pulsed with antigen. In aggregate, our data suggest that antigen-presenting-cell-independent T cell activation can effectively amplify hapten- specific immune responses.

Adult↗
PubMed2002

Nickel-specific CD4(+) and CD8(+) T cells display distinct migratory responses to chemokines produced during allergic contact dermatitis.

Development of allergic contact dermatitis to haptens depends upon a balance between CD8(+) T lymphocytes with pathogenic activity and CD4(+) T cells, which comprise both effector and regulatory cells. Thus, differential recruitment of CD8(+) and CD4(+) lymphocytes to sites of hapten challenge may have considerable impact on disease expression. Here the migration of cutaneous lymphocyte-associated antigen+, nickel-specific CD8(+) and CD4(+) T cell lines were compared with a panel of chemokines produced in the skin during allergic contact dermatitis. CCL17/TARC and CCL22/MDC induced a 3-fold higher migration of CD4(+) compared with CD8(+) lymphocytes. In contrast, CXCL10/IP-10 was 2-fold more potent in attracting CD8(+) cells. These findings were consistent with the higher expression of CCR4 and CXCR3 on CD4(+) and CD8(+) T cell lines, respectively. Moreover, CCR4 expression was high on nickel-specific T helper 2, intermediate on T helper 1 and T cytotoxic 2, and almost undetectable on T cytotoxic 1 clones. On the contrary, CXCR3 was expressed by T cytotoxic 1 and 2 and T helper 1, but not T helper 2 clones. Reverse transcription-polymerase chain reaction analysis of the skin before and after hapten challenge revealed the constitutive presence of TARC, and the early appearance of CCL2/MCP-1, followed by IP-10, CCL4/MIP-1beta, and MDC mRNA. Supernatants from activated keratinocytes induced a strong migration of CD8(+) lymphocytes, which was blocked by neutralization of IP-10. Conversely, supernatants from immature and mature dendritic cells attracted mostly CD4(+) lymphocytes in a TARC- and MDC-dependent manner. Our data indicate that distinct chemokines and cell types control the accumulation of CD8(+) and CD4(+) T cells within inflamed skin.

CD4-Positive T-Lymphocytes↗
PubMed2002

Targeting tumor necrosis factor-alpha as a potential therapy in inflammatory skin diseases.

Tumor necrosis factor-a (TNFalpha) plays an important role in the initiation and persistence of inflammation in a variety of skin disorders. The availability of selective TNFalpha blockers has provided new therapeutic opportunities. TNFa inhibitors have been employed with success in treating psoriasis in controlled trials, although further studies are warranted to better define which subgroup of patients can benefit most from this treatment and modalities of combination therapy. In addition, an increasing number of case reports indicates that anti-TNFalpha agents are of value in the treatment of other skin diseases, such as pyoderma gangrenosum and Behcet's syndrome, and in the treatment of graft-versus-host disease.

Animals↗