Biomedical subjects

L A Turka

Publications and source records attributed to L A Turka.

At least 73 records · Page 4Linked to original sources

PubMed1996

Immunosuppression through blockade of CD28:B7-mediated costimulatory signals.

It is now well established that T cells require two signals for activation and effector function. The first signal is provided through the T cell receptor for antigen. The best-characterized pathway which provides the second, or costimulatory, signal is through the CD28 receptor on the surface of T cells. In vitro, ligation of the T cell receptor without a second signal induces a long-lived state of anergy in T cells. CD28 has two known ligands, B7-1 and B7-2, expressed on activated antigen-presenting cells. A soluble fusion protein called CTLA4Ig has been produced which binds B7-1 and B7-2 and acts as a competitive inhibitor of CD28. In vitro and in vivo studies with CTLA4Ig demonstrate that it is an extremely effective immunosuppressive agent in models of transplantation and autoimmunity. Mechanistic studies indicate that CTLA4Ig may work by partially inhibiting the expansion of antigen-reactive cells and inducing anergy in the residual population.

Animals↗

PubMed1996

Preventing allograft rejection with CTLA4IG: effect of donor-specific transfusion route or timing.

BACKGROUND: Tolerance to alloantigen in transplant recipients could remove life-long dependence on immunosuppression. Evidence suggests that T-cell responses to alloantigen are dependent not only on T-cell receptor activation but also on costimulation by means of the CD28 receptor. The natural ligands for CD28, expressed on antigen-presenting cells, are B7 family members. CTLA4Ig (a soluble CD28 receptor analog) preferentially binds B7-1 and B7-2 and inhibits CD28 activation. Theoretically, T-cell receptor activation in the presence of alloantigen during CTLA4Ig blockade of CD28-B7 costimulation could render T cells tolerant to that specific alloantigen. In vivo CTLA4Ig significantly increases allograft survival times and can lead to transplantation tolerance. In the rat cardiac allograft model, donor-specific transfusion must be combined with CTLA4Ig to induce tolerance. Previously our laboratory has shown that timing is crucial in the induction of tolerance. METHODS: We examined the effect of differing routes (intravenous, portal vein, or intrathymic), as well as timing (before, at, and after transplantation), of donor-specific transfusion on its ability to synergize with CTLA4Ig using a rat heterotopic major histocompatibility complex-mismatch heart transplant model. RESULTS: We found that tolerance induced by CTLA4Ig and donor-specific transfusion was antigen specific and that timing, but not route of donor-specific antigen administration, had an impact on tolerance induction. Intravenous donor-specific transfusion had a beneficial effect on allograft survival equal to portal vein and intrathymic routes, which have been believed to be more tolerogenic. CONCLUSIONS: Almost universal engraftment can be induced with a combination of intravenous donor-specific transfusion at transplantation plus inhibition of CD28 activation by CTLA4Ig 48 hours after transplantation-a regimen which could have clinical application.

Abatacept↗

PubMed1995

CD28-B7 costimulatory blockade by CTLA4Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spares Th2 cytokines in the central nervous system.

We studied the contribution of the CD28-B7 costimulatory T cell activation pathway to the pathogenesis of experimental autoimmune encephalomyelitis in the Lewis rat model. Systemic administration of CTLA4Ig suppressed clinical disease and was effective even when CTLA4Ig was delayed until day 10 postimmunization, a time when pathologic disease is evident. This protection was not reversible by systemic administration of high doses of IL-2. Detailed immunohistologic studies showed that CTLA4Ig therapy resulted in suppression of the inflammatory response with inhibition of Th1 (IL-2 and IFN-gamma) and sparing of Th2 (IL-4, IL-10, and IL-13) cytokines in the central nervous system. These results indicate that the CD28-B7 T cell costimulatory pathway plays an important role in experimental autoimmune encephalomyelitis, a Th1-mediated disease, and suggest that blockade of this costimulatory pathway protects against active disease by causing a state of immune deviation towards Th2 function. The ability of CTLA4Ig to treat animals with pathologically established disease may have important clinical implications for patients with multiple sclerosis.

Abatacept↗

PubMed1995

CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2.

Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig-treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig-treated animals was associated with increased staining for the Th2-related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig-treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig-treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.

Abatacept↗

PubMed1995

Psoriatic skin-derived dendritic cell function is inhibited by exogenous IL-10. Differential modulation of B7-1 (CD80) and B7-2 (CD86) expression.

Regulation of immune responses depends on interactions between APCs and T cells. Such cellular interactions are mediated by surface molecules including MHC class II Ags (DR) and CD28 ligands B7-1 (CD80) and B7-2 (CD86). Recent evidence indicates that the presence or absence of costimulatory molecules on APCs significantly influences the qualitative and quantitative nature of an immune response. In this report, we analyze two relevant cytokines in skin immunobiology, granulocyte-macrophage (GM)-CSF and IL-10, and demonstrate their effects on cultured dendritic cells obtained from dermis (DDCs) of normal skin and psoriatic lesions. For comparison, the effects on these professional APCs were contrasted with cultured blood-derived monocytes. Normal and psoriatic skin-derived DDCs express high levels of CD86 over CD80, and the overall hierarchy is DR > CD86 > CD80, whereas cultured monocytes express low and equivalent levels of CD80 and CD86. If Ab is added to GM-CSF at the initial period of cultivation, DDCs that emigrate have lower levels of CD86 without any detectable effect on CD80 or DR expression and display a reduced capacity to stimulate either superantigen-driven or alloantigen-responsive T cells. Conversely, by adding GM-CSF to monocytes, CD86 levels are enhanced. When IL-10 was added at the beginning of culture, DDCs had significantly lower levels of CD86, without any effect on CD80 or DR expression, and like anti-GM-CSF-treated cells, these DDCs had approximately a 50% reduction in their T cell-stimulating capacity. In contrast, when monocytes were treated identically with exogenously added IL-10, they retained their relatively low levels of CD80 and CD86 with no detectable change in APC function. Blocking studies of DDC:T cell interaction indicated that CD86 was more important than CD80. Thus, differential expression patterns and functional cytokine responses involving these APC populations may be relevant to skin disorders such as psoriasis, in which discordant patterns of CD28 ligand expression and disordered cytokine networks are present.

Antibodies, Monoclonal↗

PubMed1995

Lymphoid expression and regulation of A20, an inhibitor of programmed cell death.

A20 is a cytokine-inducible primary response gene that encodes a protein that inhibits apoptosis. We cloned and characterized a murine A20 cDNA and mapped the gene to mouse chromosome 10, 3.5 centimorgans proximal to the c-myb locus. Using the murine cDNA, we conducted in situ hybridization studies to examine patterns of A20 expression in mouse embryos and postnatal tissues. Both temporally restricted and tissue-specific patterns of A20 expression were observed, with strikingly high levels in lymphoid organs, including the thymus, spleen, and gut-associated lymphoid tissue. Northern analysis using purified human lymphocyte populations demonstrated that A20 is constitutively expressed in both immature and mature thymocyte subpopulations, as well as in resting peripheral T cells. Activation leads to a down-regulation of A20 expression in both mature thymocytes and peripheral T cells. This pattern of expression and regulation differs markedly from that observed in prior studies with cell lines in which stimulation led to an induction of A20 expression. Additionally, this is the first demonstration of constitutive expression of A20 in primary cells. The data suggest a role for A20 in the function of the lymphoid system.

Amino Acid Sequence↗

PubMed1995

Cloning the rat homolog of the CD28/CTLA-4-ligand B7-1: structural and functional analysis.

T cell activation involves the delivery of two independent signals to the naive T cell. The first signal occurs with engagement of the TCR. One of the best characterized second signals is ligation of CD28 on the surface of T cells by B7 molecules (B7-1, B7-2) present on the surface of activated antigen presenting cells (APCs). Recent studies have demonstrated that injection of a human fusion protein, CTLA-4-Ig, which in humans binds to both B7-1 and B7-2, prevents cardiac allograft rejection in a rat transplantation model when given 48 h after engraftment. In order to better characterize the role of B7-1 (which is maximally expressed 48 h after activation of APCs) in this model, as well as in models of tumor-induced immune responses, we have cloned the rat homolog of B7-1, and now report on its structure and function. A 1030 bp cDNA containing the entire coding sequence of the rat B7-1 was cloned with a polymerase chain reaction strategy utilizing degenerate primers derived from published murine and human B7-1 sequences. The rat B7-1 coding sequence is 67 and 81% homologous to human and murine B7-1 cDNAs, and the predicted peptide sequence is likewise 57 and 66% identical to the peptide sequences of human and murine B7-1 respectively. The greatest area of identity occurs in the extracellular portion of the molecule, particularly the Ig-C like domain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1995

Direct and indirect control of T-cell activation by keratinocytes.

Keratinocytes can function as antigen-presenting cells/accessory cells and regulate T cells with three distinct outcomes, depending on the nature of the stimulus. In the presence of alloantigen, it appears that a "null" event takes place between T cells and keratinocytes, with neither activation nor induction of tolerance. Using nominal antigen, keratinocytes induce antigen-specific tolerance. In contrast, with bacterial-derived superantigens, phytohemagglutinin, or immobilized CD3 monoclonal antibody, keratinocytes can significantly activate resting autologous T-cell proliferation and cytokine release. To understand these highly divergent responses, we focused on the two-signal model of T-cell activation, with particular emphasis on costimulatory molecules expressed by keratinocytes. Such second signals, as highlighted by the B7 and CD28 receptor families, provide useful insights into the complex interactions involving keratinocytes and T cells. In this review, we summarize recent evidence indicating that keratinocytes regulate T-cell activation in a direct and indirect manner by their mutual expression and responsiveness involving adhesion molecules, cytokines, and costimulatory signals. As investigative momentum continues to grow in the fields of immunology and keratinocyte biology, it is likely that manipulation of CD28:B7 interactions will not only provide a useful model to understand further the complexities of skin immune reactions, but will also serve as the basis for new therapeutic opportunities for numerous T-cell-mediated diseases that involve aberrant reactions with keratinocytes.

Animals↗

PubMed1995

T cell costimulatory pathways: promising novel targets for immunosuppression and tolerance induction.

It is now accepted that T cells need two signals for full activation. The first is the foreign antigen itself presented by self-major histocompatibility complex and thus provides antigen specificity to the immune response. The second is a "costimulatory" signal, the best-characterized of which is provided through the T cell accessory molecule CD28. In vitro, the blockade of costimulatory signals inhibits T cell activation and induces a state of antigen-specific unresponsiveness. In vivo, agents that block CD28-mediated costimulation have proved extremely effective in inhibiting the immune response in experimental models of transplantation and autoimmune disease, providing novel strategies for use in clinical trials in the near future.

Animals↗

PubMed1995

Interleukin 12: a potential link between nerve cells and the immune response in inflammatory disorders.

BACKGROUND: The nervous system has been implicated in several inflammatory skin disorders based on evidence such as the role of stress in inducing lesions, symmetry of lesions, and sparing of denervated skin. Interleukin 12 (IL-12) is a cytokine recently shown to promote cellular immune responses characterized by delayed-type hypersensitivity and production of the TH1-lymphokine, interferon-gamma. MATERIALS AND METHODS: Using immunohistochemistry, IL-12 immunoreactivity was identified in cryostat sections of normal and diseased human skin samples, and in the peripheral and central nervous system of rodents and human tissue samples. IL-12 p35 and p40 mRNAs were detected using reverse transcriptase-polymerase chain reaction in tissue samples and cultured cells. IL-12 protein levels were also examined by ELISA and quantitative bioassay utilizing an IL-12-dependent cell line. RESULTS: By immunostaining IL-12 was detected in free nerve ending in the epidermis of normal and diseased skin samples, and also in the dermal nerve fibers. Strong reactivity was detected in axonal processes and in various glial cell types. In addition, IL-12 protein and mRNA were contained within cutaneous peripheral nerves and spinal cord tissues, and functional levels of IL-12 were produced by cultured Schwann cells. CONCLUSIONS: It is likely that IL-12 is important in initiating or propagating selected inflammatory skin lesions and in determining the pattern of disease that will develop. The presence of IL-12 in neural tissue suggests a mechanism whereby the nervous system can modify or amplify cutaneous and perhaps other immune responses.

Animals↗

PubMed1994

Bcl-2 expression during T-cell development: early loss and late return occur at specific stages of commitment to differentiation and survival.

During T-cell development CD3-CD4-CD8- (double-negative) thymocytes proliferative and produce an enormous number of CD3loCD4+CD8+ (double-positive) thymocytes which are destined to die intrathymically unless rescued by positive selection. Those which survive become mature CD3hiCD4/8+ (single-positive) cells and are the precursor of peripheral blood lymphocytes. The product of the bcl-2 protooncogene has been implicated in preventing programmed cell death and is required for prolonged lymphocyte survival following maturation. Previously we and others have reported that Bcl-2 protein expression is biphasic, being high in proliferating double-negative stem cells, low in all double-positive thymocytes except for 1-5% of these cells, and restored in mature, single-positive thymocytes. However, it remained unclear which signaling and selection events regulate Bcl-2 during T-cell maturation. Now we have utilized four-color flow cytometry in normal and genetically altered mice for a detailed analysis of Bcl-2 expression as it relates to T-cell receptor (TCR) expression and positive selection. These studies show that (i) expression of a transgenic TCR in double-negative thymocytes does not lead to premature loss of Bcl-2; thus, Bcl-2 downregulation is not solely due to TCR expression; (ii) Bcl-2 expression is lost at the early transitional CD3-/loCD4-CD8+ stage, prior to expression of CD4; (iii) the Bcl-2+ double-positive thymocytes are those which have undergone positive selection; and (iv) upregulation of Bcl-2 during positive selection requires participation of the CD4 or CD8 co-receptor. These results demonstrate that Bcl-2 and TCR expression are regulated independently during T-cell development, and suggest a role for the CD4 or CD8 co-receptor in Bcl-2 induction during positive selection.

Animals↗

PubMed1994

Keratinocyte-derived T cell costimulation induces preferential production of IL-2 and IL-4 but not IFN-gamma.

By using superantigens, we have found previously that keratinocytes activated by IFN-gamma could serve as accessory cells, providing costimulatory signals needed to induce T cell proliferation. Here, we compared the profile of cytokines produced by T cells stimulated in the presence of activated keratinocytes with the response seen using professional APCs. When keratinocytes are used as accessory cells there is a specific defect in T cell IFN-gamma production, whereas IL-2 and IL-4 are induced at levels comparable with those seen when professional APCs are used as accessory cells. Because keratinocytes express BB-1, a CD28-ligand distinct from B7-1 or B7-2 (which are found on professional APCs), we examined the possibility that the defect in IFN-gamma production might be a result of nonproductive CD28 engagement. However, even when the CD28 pathway is directly activated by a stimulatory mAb, there is no induction of IFN-gamma production in keratinocyte-supported cultures. In these same cultures IL-2 production is increased 10-fold, thus demonstrating a specific deficiency in the induction of IFN-gamma rather than a failure to respond to CD28 stimulation. Analysis by reverse transcriptase-PCR and ELISA for the inducible p40 chain of IL-12 reveals that keratinocytes produce little if any messenger RNA and no protein for IL-12 p40 compared with professional APCs. Addition of rIL-12 to keratinocyte-supported cultures restores IFN-gamma levels to those seen when professional APCs are present. Finally, when T cells are restimulated and analyzed at later time points (10 to 14 days) we find a refinement in cytokine profiles: T cells stimulated in the presence of professional APCs produced the Th1 cytokines IL-2 and IFN-gamma, whereas T cells stimulated in the presence of activated keratinocytes produced only the Th2 cytokine IL-4. The specific ability of keratinocytes to induce a Th2 response seems most closely linked to their absence of IL-12 production, and may be important in the maintenance of peripheral tolerance to self-Ags or in the immune response to exogenous Ags, pathogens, or haptens encountered in skin.

Antigen-Presenting Cells↗

PubMed1994

T lymphocytes in skin lesions of psoriasis and mycosis fungoides express B7-1: a ligand for CD28.

The activation of T cells requires two distinct signals. One signal involves interaction of the antigen-specific T-cell receptor with major histocompatibility complex molecules plus antigenic peptide; a second signal, which is antigen nonspecific, is the interaction of CD28 with its natural ligands B7-1 and B7-2/B70. CD28 is expressed on 80% of T cells, is upregulated after activation, and binds to B7 gene-family members, found on antigen-presenting cells. Because of our interest in the immunologic basis of benign and malignant T-cell-mediated disorders of the skin, we investigated the cellular distribution of CD28 and B7 family members in lesions of psoriasis and mycosis fungoides. By immunostaining cryostat sections of skin, CD28 was found to be expressed on virtually all lymphocytes in the epidermis and dermis of both skin diseases. Surprisingly, B7-1 was also found to be expressed on virtually all lymphocytes in the epidermis and dermis of both skin diseases. B7-1 expression was confirmed on CD3+ T lymphocytes using flow cytometry of single cell suspensions of fresh, unfixed psoriatic lesional tissue. To exclude the possibility that this result was caused by a second reagent contaminating the monoclonal antibody (MoAb) preparation, two different lots were used, and the MoAb was absorbed onto Chinese hamster ovary (CHO) transfectants expressing B7-1, or vector-only transfected CHO cells. These procedures confirmed that a B7-1-like epitope was being recognized on psoriatic lesional T cells. In contrast to B7-1 expression on lymphocytes, B7-3, as defined by anti-BB-1 MoAb reactivity, was found primarily on epidermal keratinocytes in both skin diseases and was not found on T cells. These results indicate that within two common skin disorders, lesional T cells accumulate in the dermis and epidermis, which express B7-1. Such expression may permit self-costimulation involving the CD28-mediated activation pathway, and thereby contribute to the ongoing T-cell proliferation present in these chronic, benign, and malignant skin diseases.

Animals↗

PubMed1994

T cell receptor stimulation, but not CD28 costimulation, is dependent on LFA-1-mediated events.

Accessory molecules play a crucial role in the development of the T cell response to antigenic challenge. In this manuscript we specifically examine the role of two accessory molecules, CD28 and LFA-1, in modulating the T cell proliferative response to a variety of stimuli. We demonstrate that the proliferation induced by staphylococcal enterotoxins A and B in combination with CD28 costimulation is dependent on LFA-1-mediated events. This requirement for LFA-1 is independent of T cell-accessory cell adhesion. Similarly, an allogeneic mixed lymphocyte reaction, which has previously been shown to be a CD28-dependent response, can be inhibited by blockade of LFA-1. This suggests LFA-1 plays an essential role in these responses, either by enhancing intercellular adhesion or by an independent signal transduction event. In contrast, when the primary activating stimulus is delivered by immobilized anti-CD3 antibody or by PMA, and the secondary stimulus by either alpha-CD28 or cell-bound CD28 ligand B7, there is no requirement for LFA-1. In addition, we demonstrate that cross-linking of LFA-1 with immobilized monoclonal antibody, or engagement of LFA-1 with ICAM-1 expressed on the surface of a CHO cell, provide an insufficient costimulus for T cell proliferation initiated by enterotoxin, immobilized alpha-CD3 or phorbol ester. Our data suggests that LFA-1, in contrast to CD28, functions not as a costimulatory molecule, but serves primarily to modulate the signal delivered through the T cell receptor.

Animals↗

PubMed1994

Costimulation of superantigen-activated T lymphocytes by autologous dendritic cells is dependent on B7.

Highly purified populations of dendritic cells (DCs) can be isolated from various tissues such as skin and blood. These sites are likely to encounter secreted toxins of bacteria such as superantigens. In vivo, DCs express the cell surface molecule B7, a counterreceptor for CD28 which provides costimulation to resting T cells. Highly purified preparations of DCs obtained from the epidermis and dermis of normal skin as well as blood were used to study the role of B7 in superantigen presentation to autologous T cells, as well as in alloantigen responses. We compared these results to those obtained with nondendritic antigen presenting cells (APCs) such as mononuclear cells derived from the Ficoll-Hypaque interface (PBMCs). All DC populations strongly express B7, and in a purely autologous system staphylococcal enterotoxin B (SEB)-mediated T cell proliferation was inhibited by 55-85% using a soluble chimeric fusion protein (i.e., CTLA4Ig), a potent inhibitor of CD28:B7 interaction. In contrast, while T cells also proliferated vigorously when stimulated by SEB in the presence of autologous PBMC (which only weakly express B7), costimulation was not inhibited by CTLA4Ig. In allogeneic responses, DCs were also more potent stimulators compared to PBMC, but both types of APC:T cell reactions were almost completely inhibited by CTLA4Ig (> 90%). For both SEB-mediated reactions and alloantigen reactions, the relative importance of LFA-1 and HLA-DR was similar between DCs and PBMCs. The data indicate that these DCs express B7, which can function in the SEB-driven response of autologous T cells, as well as in allogeneic T cell reactions. Overall, when comparing the relative costimulatory capabilities of different types of APCs, it appears the relatively low level of B7 expressed by PBMC functioned effectively in allogeneic reactions, whereas only the higher levels of B7 expressed by these DC populations functioned in SEB-mediated T cell responses.

Abatacept↗

PubMed1994

Keratinocyte interleukin-10 expression is upregulated in tape-stripped skin, poison ivy dermatitis, and Sezary syndrome, but not in psoriatic plaques.

Despite the highly diverse reaction patterns of benign and malignant skin diseases involving T lymphocytes, polymerase chain reaction analysis of cytokine mRNAs present in biopsy samples has revealed that many cutaneous responses can be categorized into essentially two discrete groups. One group exemplified by psoriasis is characterized by consistently detectable mRNAs for IL-2, IFN-gamma, and TNF-alpha, but not IL-4, IL-5, IL-10, thereby closely resembling the murine Th1-type cell-mediated response. The second group exemplified by tape-stripped skin, poison ivy dermatitis, and Sezary syndrome contains predominantly IL-4, IL-5, and IL-10 mRNAs resembling the Th2-type cytokine profile. Because of the growing interest in the immunoregulatory role of IL-10, which can suppress IFN-gamma production and inhibit cell-mediated reactions, we produced a rabbit antiserum that was used to immunohistochemically localize IL-10 in a total of 27 biopsies. The results revealed that in Th2-type skin diseases, IL-10 was predominantly identified throughout all levels of epidermis in the cytoplasm of keratinocytes (KCs), with accentuation of their membranes in upper level cells. In Sezary syndrome, T cells were also immunoreactive for IL-10, which was confirmed using the HUT 78 T cell line derived from a Sezary syndrome patient. While normal skin was devoid of IL-10 expression, KCs began expressing it as early as 6 hr following tape stripping or application of poison ivy antigen and became strongly and diffusely positive by 18-24 hr. In contrast, psoriatic plaques contained no IL-10 immunoreactivity in either the parakeratotic scale or the epidermal KCs. These results confirm the earlier IL-10 mRNA analysis using whole skin samples and immunolocalize IL-10 to epidermal KCs in the Th2 diseases.

Biopsy↗

PubMed1994

The effect of combination cyclosporine and CTLA4-Ig therapy on cardiac allograft survival.

Transplant rejection requires not only T cell receptor/CD3 complex activation by foreign MHC, but also additional costimulatory signals, as T cell receptor activation alone is insufficient for induction of the immune response. The CD28 receptor on helper T cells, interacting with its ligand B7 on activated B cells or macrophages, provides this costimulus to support T cell activity. CTLA4Ig (a soluble CD28 receptor analog), binds B7 and inhibits CD28 activation. As cyclosporine (CsA) has many side effects and CTLA4Ig alone has a significant benefit upon cardiac allograft survival, we theorized that allograft survival could be improved by using CTLA4Ig with lowered dose CsA. In vitro, high-dose CTLA4Ig inhibited the mixed lymphocyte culture reaction (MLR) between MHC-incompatible rat strains. Furthermore, there was synergistic suppression of MLR by low-dose CTLA4Ig combined with low-dose CsA. In vivo studies used a cervical heterotopic transplant model. Control recipients received no immunotherapy. Experimental recipients received low-dose CsA (1.5 mg/kg/day im) x 14 days after transplant or CTLA4Ig (10, 50, or 150 micrograms IP x 7 days). Combination animals received both CTLA4Ig and CsA. These studies showed that low doses of CsA and CTLA4Ig were additive in vivo, although no additional benefit was seen when CsA was combined with high-dose CTLA4Ig. These data suggest that the combination of low-dose CsA plus CTLA4Ig may prove useful in clinical transplantation to maximize immunosuppression and minimize side effects.

Abatacept↗

PubMed1994

Immunological functions of non-professional antigen-presenting cells: new insights from studies of T-cell interactions with keratinocytes.

T-cell activation in the absence of co-stimulatory signals can lead to induction of anergy. Professional antigen-presenting cells (APCs) of bone marrow origin, such as macrophages and dendritic cells, can provide co-stimulation through molecules such as B7-1 and B7-2. In addition, cells of epithelial origin can function as 'non-professional' APCs when activated. In these circumstances, the functional consequences of the T cell-APC interaction may differ, perhaps due to the nature of the co-stimulatory pathways utilized and/or the cytokines encountered by the T cell. Here, Brian Nickoloff and Laurence Turka suggest that these differences may be important in regulating immune responses to local antigens and also in maintaining self-tolerance.

Animals↗