Mecanismo de acción de abatacept: concordancia con su perfil clínico / Abatacept mechanism of action: concordance with its clinical profile

La interacción molecular doble y simultánea entre las células presentadoras de antígeno (CPA) y los linfocitos T es imprescindible para la activación óptima de la respuesta inmunitaria y requiere de la participación de dos grupos de receptores de membrana. El abatacept es una proteína de fusión que modula selectivamente una de estas dos vías, uniéndose a los receptores CD80 y CD86 de las CPA. De esta forma el fármaco inhibe la activación de las células T, bloqueando selectivamente la unión específica de los receptores CD80/CD86 al CD28 y como consecuencia inhibiendo la proliferación de las células T y la respuesta inmunitaria de las células B. Esta acción farmacológica se traduce en la normalización de los niveles de los mediadores inflamatorios en los enfermos con artritis reumatoide y en una respuesta clínica segura y eficaz. El abatacept, en combinación con metotrexato, evita la progresión de la lesión articular y mejora la función física en enfermos con artritis reumatoide (AU)

The double and simultaneous molecular interaction between antigen-presentig cells (APC) and T lymphocytes is essential for the optimal activation of the immunological response and requires the participation of two membrane receptor groups. Abatacept is a fusion protein that selectively modulates one of these two ways, by binding to CD80 and CD86 receptors on APC. In this way, the drug inhibits T cell activation, selectively blocking the specific interaction of CD80/CD86 receptors to CD28 and, therefore, inhibiting T cell proliferation and B cell immunological response. This pharmacological action results in the normalization of inflammatory mediators in rheumatoid arthritis patients and in a safe and efficacious clinical response. Abatacept in combination with methotrexate prevents the progression of joint damage and improves physical function in rheumatoid arthritis patients (AU)

[Inhibition of tumor growth in rat liver induced by tumor-specific transfer factor].

A transfer factor (TF) specific to antigens of Geren's carcinoma in rat was developed using an original model of intraorganic growth. Intravenous injection (1pg/g body) inhibited primary tumor node growth in the liver by 78% and blocked dissemination to peritoneal viscera. Its effect was due to an immunospecific component promoting antitumor immunological response. The latter presented as generation of cytotoxic effector cells, vascular disorders in tumor parenchyma thus blocking tumor cell proliferation. Possible applications of tumor-specific TF for biotherapy of cancer patients are discussed.

Recombinant dimeric MHC antigens protect cardiac allografts from rejection and visualize alloreactive T cells.

Monomeric and dimeric soluble major histocompatibility complex (MHC) molecules down-regulate activated T cells in an antigen-specific manner in vitro. This property could be exploited to modulate alloresponses in vivo but has remained difficult to demonstrate. Here, intraperitoneal infusion of a Lewis-derived rat MHC class I molecule, RT1.A(l)-Fc, in Dark Agouti (RT1.A(a)) recipient rats prolonged cardiac graft survival, which led to permanent engraftment. This effect was mediated by T cell impairment of target cell lysis by CD8+ T cells and down-regulation of interferon-gamma production by CD4+ T cells. The binding of the dimeric MHC allowed ex vivo visualization of alloreactive T cells in peripheral blood, splenocytes, and allografts, revealing low frequency of alloreactive CD8+ T cells after establishment of permanent engraftment of cardiac allografts. Thus, these data show the potential of dimeric MHC molecules to promote graft survival and allow visualization of alloreactive T cells.

Fenotipos HLA en niños celliacos y en familiares de primer grado. Estudio comparativo poblacional / HLA phenotypes in children with celiac disease and first-degree family members a comparative population-based study

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Human CD1d functions as a transplantation antigen and a restriction element in mice.

To study the potential functions of human CD1d (hCD1d), we developed transgenic (Tg) mice that ectopically express hCD1d under the control of H-2K(b) promoter. High levels of hCD1d expression were detected in all Tg tissues tested. Skin grafts from the K(b)/hCD1d Tg mice were rapidly rejected by MHC-matched non-Tg recipient mice, suggesting that hCD1d can act as transplantation Ags. Furthermore, we were able to elicit hCD1d-restricted CD8(+) CTLs from mice immunized with K(b)/hCD1d Tg splenocytes. These CTLs express TCR rearrangements that are distinct from invariant TCR of NK T cells, and secrete significant amounts of IFN-gamma upon Ag stimulation. Analysis with various hCD1d-expressing targets and use of Ag presentation inhibitors indicated the recognition of hCD1d by CTLs did not involve species or tissue-specific ligands nor require the processing pathways of endosomes or proteasomes. Additionally, the reactivity of hCD1d-specific CTLs was not affected by acid stripping followed by brefeldin A treatment, suggesting that CTLs may recognize a ligand/hCD1d complex that is resistant to acid denaturation, or empty hCD1d molecules. Our results show that hCD1d can function as an alloantigen for CD8(+) CTLs. The hCD1d Tg mice provide a versatile model for the study of hCD1d-restricted cytolytic responses to microbial Ags.

Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells.

Blockade with B7 antagonists interferes with CD28:B7 and CTLA-4:B7 interactions, which may have opposing effects. We have examined the roles of CD28:B7 and CTLA-4:B7 on in vivo alloresponses. A critical role of B7:CD28 was demonstrated by markedly compromised expansion of CD28-deficient T cells and diminished graft-versus-host disease lethality of limited numbers of purified CD4+ or CD8+ T cells. When high numbers of T cells were infused, the requirement for CD28:B7 interaction was lessened. In lethally irradiated recipients, anti-CTLA-4 mAb enhanced in vivo donor T cell expansion, but did not affect, on a per cell basis, anti-host proliferative or CTL responses of donor T cells. Graft-versus-host lethality was accelerated by anti-CTLA-4 mAb infusion given early post-bone marrow transplantation (BMT), mostly in a CD28-dependent fashion. Donor T cells obtained from anti-CTLA-4 mAb-treated recipients were skewed toward a Th2 phenotype. Enhanced T cell expansion in mAb-treated recipients was strikingly advantageous in the graft-versus-leukemia effects of delayed donor lymphocyte infusion. In two different systems, anti-CTLA-4 mAb enhanced the rejection of allogeneic T cell-depleted marrow infused into sublethally irradiated recipients. We conclude that blockade of the selective CD28-B7 interactions early post-BMT, which preserve CTLA-4:B7 interactions, would be preferable to blocking both pathways. For later post-BMT, the selective blockade of CTLA-4:B7 interactions provides a potent and previously unidentified means for augmenting the GVL effect of delayed donor lymphocyte infusion.

Mechanisms of oral tolerance by MHC peptides.

Recent evidence indicates that MHC peptides play an important role in T-cell recognition of alloantigen. We studied the tolerogenicity of orally administered synthetic MHC allopeptides in the rat model. Initially, we demonstrated that oral administration of synthetic class II MHC allopeptides significantly inhibited the DTH response to the peptides as well as to donor-derived cells. The tolerogenic effect was antigen specific and was induced by immunogenic, but not by nonimmunogenic, allopeptides. Immunohistological studies of DTH skin lesions showed that oral tolerance is associated with a state of "immune deviation" to a predominance of Th2 cell function in the lesions. We recently extended the above observations and examined the tolerogenic effect of orally administered synthetic MHC allopeptides on MLR and CTL generation. We found that oral administration of the class II allopeptides effected significant reduction of MLR proliferation and CTL generation, which was antigen specific. In addition, similar to the DTH results when we compared the tolerogenicity of the immunogenic versus the nonimmunogenic peptides, MLR and CTL suppression was significantly higher with the immunogenic peptides. The gut immune system play an important role in oral tolerance by MHC peptides. Initial experiments showed that intestinal epithelial cells pulsed in vitro with immunogenic MHC allopeptides, or in vivo by oral administration of immunogenic peptides, were capable of presenting these peptides to primed T cells in vitro. Whether such presentation by intestinal epithelial cells or other gut antigen-presenting cells leads to preferential activation of Th2 regulatory cells, which ultimately suppress Th1 alloimmune responses, remains to be determined.

Rat intestinal epithelial cells present major histocompatibility complex allopeptides to primed T cells.

BACKGROUND/AIMS: Intestinal epithelial cells present protein antigens to primed T cells in vitro. The aim of this study was to investigate whether intestinal epithelial cells present peptide antigens in vitro and in vivo after oral administration. METHODS: Small intestinal epithelial cells from naive LEW (RT1) rats pulsed in vitro with a synthetic immunogenic major histocompatibility complex allopeptide, RT1.Du beta 20-44, or in vivo by oral administration of the peptide were tested for their ability to induce specific proliferation of LEW T cells primed in vivo to RT1.Du beta 20-44. RESULTS: In vitro pulsed intestinal epithelial cells induced specific proliferation of RT1.Du beta 20-44-primed T cells. Intestinal epithelial cells isolated from LEW ras that received a single oral dose of RT1.Du beta 20-44 18 hours earlier also induced specific proliferation of RT1.Du beta 20-44-primed LEW T cells. Furthermore, epithelial cells harvested from LEW rats that received WF (RT1u) splenocytes orally 18 hours earlier induced specific proliferation of RT1.Du beta 20-44-primed LEW T cells. CONCLUSIONS: Intestinal epithelial cells take up processed alloantigen in vitro and in vivo for presentation as peptides to primed T cells. These observations provide a novel approach to study the role of the intestinal immune system in immune regulation in vivo.

Effect of graft perfusion with two CD45 monoclonal antibodies on incidence of kidney allograft rejection.

In a blind trial, 77 patients were randomised to receive first cadaver kidney allografts that had been perfused either with a pair of CD45 monoclonal antibodies (mAbs), in an attempt to reduce the immunogenicity of passenger leucocytes, or with control human albumin solution. No complications of mAb perfusion were observed. Patient and allograft survival were similar in both groups. Rejection episodes were recorded in 7 (18%) of the patient with mAb perfused allografts compared with 24 (63%) of the controls.

Effect of continuous administration of interleukin 2 on active specific chemoimmunotherapy with extracted tumor-specific transplantation antigen and cyclophosphamide.

Injection of purified human interleukin 2 (IL-2) directly into the spleen has been shown to potentiate the effect of specific chemoimmunotherapy, using butanol-extracted tumor-specific transplantation antigen (TSTA) and cyclophosphamide (CY) in a C3H/HeJ murine methylcholanthrene-induced fibrosarcoma model. Since IL-2 has a relatively short half-life in serum, continuous infusion of this lymphokine via the intrasplenic (i.s.), i.v., or i.p. routes was administered in an attempt to maintain therapeutic tissue levels. Primary hosts bearing 7-day (4-mm) or 14-day (greater than 10-mm) established s.c. methylcholanthrene F tumors were treated with weekly s.c. doses of 1 micrograms 1-butanol-extracted, isoelectrophoretically purified TSTA, the first of which was combined with a single i.p. injection of 20 mg/kg CY, and/or a 10-day continuous infusion of 120 units IL-2/day by one of the three routes. IL-2 delivered by all routes either by continuous infusion or by bolus injection augmented the chemoimmunotherapeutic efficacy of TSTA/CY against 7-day established tumors. On the other hand, the outcome of 14-day (greater than 10-mm) established tumors depended upon the method and route of administration of IL-2: continuous infusion via the i.v., i.p., or i.s. route prolonged host survival beyond that obtained by bolus administration. Continuous i.s.-IL-2 infusion greatly prolonged, continuous i.p.-IL-2 (120 units/day) slightly extended, and continuous i.v.-IL-2 had no effect on host survival. In a spontaneous pulmonary metastasis model following amputation of a tumor-bearing limb, only the triple regimen of TSTA/CY/i.s.-IL-2 decreased the number of lung colonies and prolonged host survival. Continuous infusion i.s.-IL-2 (120 units/day, 10 days) combined with TSTA/CY induced tumor-specific cytotoxic T-cells, as documented by in vitro 51chromium release cytolytic and in vivo local adoptive transfer assays. Based upon the residual local adoptive transfer assay activity of spleen cells depleted of specific lymphocyte subpopulations using monoclonal antibodies, the immune effectors generated by i.s.-IL-2 plus TSTA/CY bear the Thy 1+, Lyt2+ phenotype and those by i.p. or i.v.-IL-2 plus TSTA/CY, the Thy+, L3T4+ markers. Thus continuous i.s.-IL-2 infusion appears to augment cytotoxic T-cell induction in tumor-bearing hosts undergoing stimulation of helper elements by TSTA and inhibition of suppressor cells by CY.

Bulk purification of a naturally occurring soluble form of RT1-A class I major histocompatibility complex antigens from DA rat liver, and studies of specific immunosuppression.

We describe the bulk purification of a water-soluble form of RT1-A class I MHC antigens from aqueous extracts of DA liver. Using a combination of monoclonal antibody affinity, lentil lectin affinity, and gel permeation chromatography, we were able to obtain large quantities of pure water-soluble RT1-A antigens. Typically, from 40 DA livers, 0.5 mg of pure antigen with antigen activity equivalent to 7 X 10(9) nucleated DA spleen cells was obtained. The water-soluble RT1-A molecule had a discrete heavy chain of 40 kD, linked noncovalently to beta 2 microglobulin. The heavy chain of the water-soluble RT1-A molecule was 5 kD smaller than the membrane-bound form of RT1-A from DA liver membranes. The smaller molecule probably represents a secreted form of RT1-A class I molecules that lack the transmembrane domain (exon 5). Large quantities of this water-soluble RT1-A class I antigen from the DA strain, given intravenously to PVG recipients of DA cardiac allografts by a variety of protocols, did not have any effect on graft survival. The fairly ready availability of milligram quantities of pure class I transplantation antigens should be of considerable value for studies in transplantation.