Cell Receptor Monoclonal Antibody Research Articles

The Vbeta13 T Cell Receptor Monoclonal Antibody Reduces Hyaluronan and CD68+, CD3+, and CD8+ Cell Infiltrations to Delay Diabetes in Congenic BB DRLyp/Lyp Rats.

The depleting Vβ13a T cell receptor monoclonal antibody (mAb) 17D5 prevents both induced and spontaneous autoimmune diabetes in BB rats. Here it was tested in congenic DRLyp/Lyp rats, all of which spontaneously developed diabetes. Starting at 40 days of age, rats were injected once weekly with either saline, His42 Vβ16 mAb, or 17D5 mAb and monitored for hyperglycemia. Diabetes occurred in 100% (n = 5/5) of saline-treated rats (median age, 66 days; range 55–73), and in 100% (n = 6/6) of His42-treated rats (median age, 69 days; range 59–69). Diabetes occurred in fewer (n = 8/11, 73%) 17D5-treated rats at a later age (median 76 days, range 60–92). Three (27%) of the 17D5-treated rats were killed at 101–103 days of age without diabetes (17D5 no-diabetes rats). Survival analysis demonstrated that 17D5 mAb delayed diabetes onset. Saline- and His42-treated rats had severely distorted islets with substantial loss of insulin-positive cells. These rats exhibited prominent hyaluronan (HA) staining, with the intra-islet HA+ accumulations measuring 5,000 ± 2,400 µm2 and occupying 36 ± 12% of islet area, and severe (grade 4) insulitis with abundant infiltration by CD68+, CD3+, and CD8+ cells. The 17D5 mAb-treated rats with delayed diabetes onset exhibited less severe insulitis (predominantly grade 3). In contrast, the 17D5 no-diabetes rats had mostly normal islets, with insulin+ cells representing 76 ± 3% of islet cells. In these rats, the islet HA deposits were significantly smaller than in the diabetic rats; the intra-islet HA+ areas were 1,200 ± 300 µm2 and accounted for 8 ± 1% of islet area. Also, islet-associated CD68+ and CD3+ cells occurred less frequently (on average in 60 and 3% of the islets, respectively) than in the diabetes rats (present in >95% of the islets). No CD8+ cells were detected in islets in all 17D5 no-diabetes rats. We conclude that mAb 17D5 delayed diabetes in DRLyp/Lyp rats and markedly reduced expression of HA and concomitant infiltration of CD68+, CD3+, and CD8+ cells. Our findings underscore the importance of refining immune suppression in prevention or intervention clinical trials to use mAb reagents that are directed against specific T cell receptors.

Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant

In this study, we investigated the mouse dendritic cell (DC) receptor, complement receptor 4 (CR4; CD11c/CD18), as an immunotarget for triggering humoral immunity. Comparison of antibody titres generated against a panel of 13 anti-antigen-presenting cell receptor monoclonal antibodies, with or without conjugated ovalbumin (OVA), revealed uniquely rapid and robust responses following CR4 targeting, with antibody titres approaching 1 : 100 000 7 days after a single dose of antigen. Furthermore, using just 100 ng OVA conjugated to anti-CD11c Fab', we generated anti-OVA titres greater than those produced by a 100-fold higher dose of OVA in complete Freund's adjuvant at day 28. These anti-OVA antibody titres were sustained and could be boosted further with targeted OVA on day 21. Investigations to explain this vaccine potency showed that, in addition to targeting splenic DC, anti-CDl1c antibodies delivered a powerful adjuvant effect and could boost humoral immunity against OVA even when the OVA was targeted to other molecules on DC, such as major histocompatibility complex class II, CD11a and CD11b. However, interestingly, this adjuvant effect was lost if OVA was targeted to other cells such as B cells via CD21 or CD19. The adjuvant effect was mediated through a marked enhancement of both germinal centre and extrafollicular plasma cell formation in responding spleens. These results demonstrate that anti-CD11c monoclonal antibody can both target antigen and act as a powerful adjuvant for rapid and sustained antibody responses. They also point to an interesting role for CR4 on DC in triggering B cells during humoral immunity.

Transgene Persistence and Cell Turnover in the Diarthrodial Joint: Implications for Gene Therapy of Chronic Joint Diseases

Local gene therapy for chronic joint diseases requires prolonged transgenic expression, but this has not been reliably achieved in animal models. Using normal and immunocompromised animals, we examined the capacity of various cell types in joint tissues to maintain and express exogenous transgenes after direct intra-articular gene delivery. We found that transgenic expression could persist for the lifetime of the animal but required precise immunological compatibility between the vector, transgene product, and host. It was not dependent on vector integration or promoter origin. We identified two phenotypically distinct sub-populations of genetically modified cells within the joint: (i) transient cells, with a half-life of a few weeks, and (ii) stable cells that reside in the joint tissues indefinitely. Contrary to the prevailing assumption, the transient sub-population was composed almost exclusively of synovial fibroblasts, indicating that the synovium is not an appropriate tissue upon which to base a long-term therapy. Instead, fibroblasts in the ligaments, tendons, and capsule emerged as the primary cell types capable of sustained therapeutic transgene expression. This study sheds new light on the cellular dynamics of articular tissues and suggests that cell turnover and immune reactivity are the key determinants in achieving sustained transgenic expression intra-articularly.

Short-form Ron receptor is required for normal IFN-γ production in concanavalin A-induced acute liver injury

Abrogation of Ron receptor tyrosine kinase function results in defects in macrophage activation and dysregulated acute inflammatory responses in vivo. Several naturally occurring constitutively active alternative forms of Ron have been identified, including from primary human tumors and tumor cell lines. One of these alternative forms, short-form (SF) Ron, is generated from an alternative start site in intron 10 of the Ron gene that eliminates most of the extracellular portion of the receptor and is overexpressed in several human cancers. To test the physiological significance of SF-Ron in vivo, mice were generated that solely express the full-length form of Ron (FL-Ron). Our results show that elimination of the capacity to express SF-Ron in vivo leads to augmented production of IFN-gamma from splenocytes following stimulation ex vivo with either concanavalin A or anti-CD3/T cell receptor monoclonal antibody. Moreover, in a concanavalin A-induced murine model of acute liver injury, FL-Ron mice have increased production of serum INF-gamma and serum alanine aminotransferase levels and worsened liver histology and overall survival compared with wild-type control mice. Taken together, these results suggest for the first time that SF-Ron impacts the progression of inflammatory immune responses in vivo and further support a role for the Ron receptor and its various forms in liver pathophysiology.

216. Development of donor specific chimerism and tolerance in composite tissue allografts under ab-t cell receptor monoclonal antibody and cyclosporine a treatment protocols

Purpose Recently, we induced donor specific tolerance to rat hind-limb allografts under 35 days course of ab TCR mAb and Cyclosporine A. In this report, we investigated the role of shorter ab-TCR/CsA protocols on the tolerance induction. Materials and Methods We performed fifty-two hind-limb transplantations, between Lewis-Brown-Norway (LBN, F1) donors and Lewis recipients to test the impact of 21, 7 and 5 day protocols of combined ab-TCR/CsA treatment on tolerance induction. Donor specific tolerance and immunocompetence were tested by mixed lymphocyte reaction (MLR) in vitro and by standard skin grafting in vivo. The efficacy of immunosuppressive protocol and donor specific chimerism was assessed by flow cytometry. Results All transplants under 5,7, and 21 days of combined ab-TCR/CsA therapy survived over 350 days. Clinical tolerance and immunocompetence were confirmed by skin grafting in vivo and MLR in vitro. Flow cytornetry revealed high level of donor chimerism in the peripheral blood of the long term survivors. Conclusion The extention of survival of limb allografts and allounresponsiveness were directly associated with the development of stable chimerism in the tolerated recipients.

217. Thymic dependence of tolerance in vascularized composite tissue allografts under Cyclosporine A and ab-T Cell Receptor monoclonal antibody protocol

Background In our previous studies, we have demonstrated that vascularized composite tissue allograft transplants treated with ab-TCR) monoclonal antibody (mAb) and Cyclosporine A (CsA) for 7 days developed robust tolerance across MHC barrier. In this paper we have investigated the role of host thymus in the induction ot tolerance in rat hind-limb allograft model. Material and Methods Five weeks old, euthymic (group A) and thymectomized (group B) Lewis recipients (LEW,RT1l) received vascularized hind-limb allografts from Lewis-Brown-Norway (LBNŕF1, RT1l+n) donors. Group lA (n=6) and 1B (n=6) and Group IIA (n=6) and IIB (n=6) served as the isograft and the allograft control groups, respectively. Groups IIIA (n=5) IIIB (n=5) and IVA (n=5) and IVB (n=5) received monotherapies of either ab-TCR mAb or CsA tor 7 days, respectively. In Groups VA(n=6) and VB (n=6) a treatment protocol of combined ab-TCR/CsA was applied for 7 days. Mixed lymphocyte reaction (MLR) and skin grafting were performed for the evaluation of the donor specific tolerance in vitro and in vivo, respectively. Flow cytometry analysis was applied for the determination of the efficacy ot immunosuppressive treatment and the presence of mixed donor specific, hematopoietic chimerism. Results Combined treatment with ab-TCR/CsA protocol resulted in indefinite survival of the euthymic rats from group VB (>100 days) and extended the survival of the animals from group VA up to 51 days, post-transplant. MLR showed donor specific tolerance in the group VA at day 100. Flow cytometry revealed stable, multillinege chimerism in the peripheral blood of euthymic rats (CD4+/RT1n–17.3% and CD8+/RT11n–13.9%) and transient chimerism in thymectiomized limb allograft recipients. Conclusions Thymus is necessary for the induction ot donor specific tolerance under ab-TCR/CsA protocol in vascularized composite tissue allograft model. Tolerogenic activity of the thymus resulted in the creation ot stable mixed hematopoietic macrochimeric state within recipient.

Effects of dietary fatty acids on burn-induced immunosuppression

Previous studies from our laboratory established that low-fat diets prevent immunosuppression and reduce oxidative stress after a thermal injury. The purpose of the present study was to test the hypothesis that the type of dietary fatty acid influences splenocyte proliferation and oxidative stress following a burn injury. Female C3H/HeN mice were fed ad libitum six experimental diets (5% w/w lipids) differing in fatty acid composition for 10 days following a burn injury. Compared to the controls, burned mice fed whichever diet showed lower lymphoproliferative responses to concanavalin-A (Con-A) and lipopolysaccharide (LPS) ( p<0.01), but not to an anti-T cell receptor monoclonal antibody (H-57). In burned animals, nitric oxide (NO) concentration was negatively correlated to the proliferation induced by Con-A ( p<0.01) or LPS ( p<0.05). These results suggest that: (1) dietary fatty acid type does not influence the splenocyte proliferation or oxidative stress and (2) NO production is involved in the immunosuppression following burn injury.

Suppression of Experimental Autoimmune Uveoretinitis by Anti- αβ TCR Monoclonal Antibody

Purpose: To evaluate the effects of anti-αβ T cell receptor monoclonal antibody (R73) on the induction of experimental autoimmune uveoretinitis (EAU) in rats. Methods: Lewis rats in which EAU was induced were treated with R73. All rats were examined for the clinical course of EAU, pathological findings of the globe, delayed-type hypersensitivity, and the interleukin-2 (IL-2) gene and protein expression in the eye. Results: The R73 treatment was effective for delaying EAU onset, decreasing the severity of EAU, and suppressing delayed-type hypersensitivity to the antigen. IL-2 gene and protein expression was reduced by R73 treatment in the anterior and posterior segments of the eye. Conclusion: R73 treatment is effective for suppression of the development of EAU, inhibiting IL-2 expression in the eye.

Liver transplant recipient sera derived soluble HLA mediates allele specific CTL apoptosis.

Significant levels of donor soluble human leukocyte antigen (HLA) class I (sHLA) are present in patients after transplants. We investigated the possibility that sHLA may inhibit cytolytic T lymphocyte (CTL) activity by inducing apoptosis of the CTL, thereby serving as a mechanism for specific tolerance. sHLA-A2 and A3 were isolated from the sera of liver transplant recipients by affinity chromatography. T cell bulk lines directed against HLA-A2 and HLA-A3 were generated by stimulation with HLA-A2, A3+ peripheral blood leukocytes and B-lymphoblastoid cells. Induction of T cell apoptosis by sHLA was analyzed by adding sHLA to allospecific CTL 4 or for 24 hr before flow cytometric analysis of propidium iodide and fluorescein isothiocyanate-conjugated annexin V stained cells. T cell receptor (TCR) engagement by sHLA was demonstrated using a monoclonal antibody specific for the TCR. sHLA-A3 inhibited CTL activity of a HLA-A3 T cell line by 53%, whereas sHLA-A2 had no effect. sHLA-A3 also increased T cell death by 77% over the control, whereas sHLA-A2 had no significant effect. However, sHLA-A2 induced 21% apoptosis of an anti-HLA-A2 T cell line, whereas sHLA-A3 caused only 3% apoptosis. The antibody complexed form of sHLA was ineffective in the induction of apoptosis. Preincubation of the T cells with anti-T cell receptor monoclonal antibody protected the T cells from sHLA-induced apoptosis, indicating that sHLA-TCR engagement is necessary for this process to occur. TCR-mediated apoptosis of alloreactive CTL may serve as a mechanism by which sHLA can modulate the immune response.

Suppression of allograft rejection with anti-alphabeta T cell receptor antibody in rat corneal transplantation.

Anti-alphabeta T cell receptor monoclonal antibody (R73) has been reported to be a potent immunosuppressant. The suppressive effects of this antibody on allograft rejection after corneal transplantation are unknown. Orthotopic rat penetrating keratoplasty was performed using Lewis rats as recipients and Brown Norway and Fisher rats as donors. The treated groups received R73 intraperitoneally until day 12 after the transplantation. In grafted rats with or without R73 treatment, cytokine expression of the aqueous humor, corneal-infiltrating cells, draining lymph nodes, and splenocytes was determined. Delayed-type hypersensitivity (DTH) responses were compared. All allografts in the untreated controls of Fisher-to-Lewis or BN-to-Lewis rat combinations were rejected within 14 days. In contrast, indefinite survival rates of the postoperative R73-treated group increased to 86% in the Fisher-to-Lewis and 23% in the Brown Norway-to-Lewis combinations, respectively. Interferon-y, interleukin (IL)-2 (T helper [Th]1), and IL-10 (Th2), but not IL-4 (Th2), expression of the eye and DTH responses in the control group were suppressed in the R73-treated group. Both IL-2 and IL-10 expression after mixed lymphocyte culture in the R73-treated group were significantly lower than those of the naive and untreated control group. alphabeta T cell receptor-targeted therapy prevents allograft rejection in rat corneal transplantation as evidenced by suppression of DTH responses. The cytokine profile after R73 treatment was characterized by low interferon-gamma, IL-2, and IL-10, and high IL-4 expression.

Anti-αβ-T cell receptor monoclonal antibody induces tolerance without dominant infiltration by TH2 cells into grafts

Anti-αβ-T cell receptor monoclonal antibody induces tolerance without dominant infiltration by TH2 cells into grafts

Different cd3/t cell receptor monoclonal antibodies have distinct capacities to induce adhesion of T lymphocytes to endothelium

Murine CD3/T cell receptor (TCR) monoclonal antibodies (mAbs) induce immediate peripheral lymphocytopenias of different degree and duration. Lymphocytopenia is of short duration after the administration of immunoglobulin A CD3 mAb, but it persists much longer after the administration of immunoglobulin G2a CD3 mAb. Peripheral lymphocytopenia after the administration of WT31, a murine immunoglobulin G1 TCR mAb, appears to be dependent on the polymorphism of FcγRlla. In high responders, lymphocytopenia is comparable to that observed after immunoglobulin G2a CD3 mAb; in low responders, no lymphocytopenia occurs. In vitro, both immunoglobulin A and immunoglobulin G2a CD3 mAbs induce immediate activation of CD11a/CD18, with concomitant up-regulation of CD11b/CD18 on T cells, each of which is shown to be involved in the concurrent adhesion of T cells to endothelium. WT31 induces an immediate activation of CD11a/CD18 as well as T cell adhesion to endothelium in FcyRlla high responders only, interestingly without changes in the level of expression of CD11b/CD18. We conclude that the immediate occurrence of peripheral lymphocytopenia after the administration of CD3/TCR mAb is mediated by changes in the level of expression or avidity (or both) of adhesion molecules on T cells, whereas the persistence of this lymphocytopenia depends on the isotype of the CD3/TCR mAb and on the presence of suitable Fc receptors.

Anti-T cell receptor monoclonal antibody prolongs transgene expression following adenovirus-mediated in vivo gene transfer to mouse synovium.

There are no cures for rheumatoid arthritis (RA) or other inflammatory autoimmune arthropathies. Gene transfer to the synovium would allow administration of anti-inflammatory gene products directly to the articular space where they could exert a local down-regulatory effect on the autoimmune process. Several well-characterized murine models of arthritis closely resemble RA immunologically, genetically, and histopathologically. To determine whether the mouse could serve as a model for gene transfer to the synovium, a methodology was developed to reproducibly inject a 5-microliter volume into the articular space of the mouse knee. Using this approach, Av1LacZ4, an E1a-E3-deleted adenoviral (Ad5) vector expressing the lacZ transgene, was delivered intra-articularly (5 x 10(8) pfu). lacZ expression was observed in the articular synovium for at least 14 days. Biochemical quantitation demonstrated a gradual loss of transgene expression, associated with an early, predominantly neutrophilic, inflammatory response that progressed to a lymphocytic infiltrate, followed by gradual resolution over a 3-week period. Pretreatment with the anti-TCR monoclonal antibody (mAb) H57 resulted in a significant reduction in lymphocytic infiltration and a prolongation of transgene expression. These data demonstrate that transgenes can be delivered to the mouse knee joint space, affording a powerful tool to test the potential of gene therapy as a therapeutic modality for RA. As in other systems, the immune response against recombinant adenoviral vectors may limit the extent and duration of gene expression in the synovium. Anti-T cell mAbs may be useful in inhibiting this immune response.

(-)-Indolactam V-Induced Mitogenesis in Human Fetal/Neonatal and Adult T Cells: Lower Response of Neonatal Cells and Possible Regulatory Role of Monocytes in Protein Kinase C-Mediated Pathways

(-)-Indolactam V (ILV) is a synthetic analog of the teleocidins, a newly described class of tumor promoters. Here we describe the mitogenic and comitogenic effect of (-)-ILV on human adult and fetal/neonatal (cord) lymphocytes. (-)-ILV induced proliferation in a dose-dependent manner, with optimal concentrations between 2.6 and 5.2 μ M. Cord lymphocytes gave significantly lower (-)-ILV responses compared to the corresponding a2ult cells (50-60% lower at optimal mitogenic doses). The mitogenic action of (-)-ILV was apparently independent of the presence of adherent monocytes. H-7, a relatively specific protein kinase (PK) C inhibitor, and H-8, a less specific PK inhibitor, suppressed (-)-ILV-induced proliferation by 54 and 36%, respectively. Suboptimal concentrations of (-)-ILV were strongly mitogenic for both adult and cord lymphocytes when added together with calcium ionophore A23187, phytohemagglutinin, or the anti-T cell receptor monoclonal antibodies OKT3 and TCR1. In adult cells, the synergistic effect decreased with increasing concentrations of (-)-ILV or/and the other comitogens, and was, in most (>60%) cases, converted to inhibition at the combination of optimal doses. The inhibition was invariably reversed by depletion of monocytes. In contrast, among cord lymphocytes (-)-ILV and OKT3 or TCR-1 showed strong cooperative effect at all concentrations tested. The (-)-ILV hyporesponsiveness and distinct comitogenic pattern of cord lymphocytes, together with the previously described lower cord cell response to phorbol ester TPA, suggest functional differences in signal transduction mechanisms between cord (naive) and adult (memory) T cells, possibly at the level of monocytes.

Immune system of the spontaneously hypertensive rat: II. Morphology and function

The spontaneously hypertensive rat (SHR) is a stress-sensitive animal which exhibits moderate immune dysfunction that has been implicated in the onset of hypertension. In this study, we examined the morphology of SHR thymus and spleen and further characterized the immune deficiency using Wistar-Kyoto (WKY) and Fisher 344 (F-344) rats for comparison. The adult SHR thymus does not display the increase in medullary volume typically noted with aging and the volume density of the marginal zone is decreased in the spleen. In vivo tritiated-thymidine incorporation is also decreased in the spleen of unstimulated SHR. In mixed lymphocyte reactions (MLR), the proliferative response of SHR splenocytes is significantly decreased relative to controls, WKY and F-344. Addition of interleukin-1 (IL-1), interleukin-2 (IL-2), or indomethacin to the MLR cultures does not increase proliferation. The proliferative response to T cell receptor monoclonal antibody (mAb-TCR) or interleukin-2 (IL-2) are similarly impaired in the SHR. The depressed proliferative T cell response is reversed by prolactin. It is suggested that the SHR is a valuable model for the study of immune deficiency.

Intercellular interactions and cytokine responsiveness of peritoneal alpha/beta and gamma/delta T cells from Listeria-infected mice: synergistic effects of interleukin 1 and 7 on gamma/delta T cells.

Peritoneal gamma/delta T cells from Listeria-immune mice show an enhanced potential to expand when restimulated with antigens or mitogens in vitro (see companion paper [Skeen, M. J., and H. K. Ziegler. 1993. J. Exp. Med. 178:971]). When cocultured with peritoneal alpha/beta T cells, the gamma/delta T cell population expanded preferentially even when the in vitro stimulus was specific for the alpha/beta T cell population. Purified gamma/delta T cells did not respond to alpha/beta T cell-specific stimuli. If isolated T cell subsets were recombined in cell mixing experiments, the resulting proliferative response was greater than additive. Irradiated alpha/beta T cells could enhance the proliferation of responding gamma/delta T cells, but the effect was unidirectional; i.e., irradiated gamma/delta T cells did not stimulate responding gamma/delta T cells. This effect appeared to be cytokine mediated and did not require cell-cell contact. Both recombinant interleukin 2 (rIL-2) and rIL-7 could support the expansion of the gamma/delta T cells, while rIL-7 was only minimally stimulatory for the alpha/beta T cells. The magnitude of the response by gamma/delta T cells to rIL-7 exceeded the response to other in vitro stimuli, including immobilized anti-T cell receptor monoclonal antibody, and was 50-100-fold greater than the alpha/beta T cell response to IL-7. This unique sensitivity of gamma/delta T cells to IL-7 was strongly enhanced by the presence of accessory cells. These cells could be replaced by rIL-1, establishing a synergy for IL-1 and IL-7 as factors that could uniquely stimulate this gamma/delta T cell population. Isolated peritoneal gamma/delta T cells from Listeria-immune mice react to heat-killed Listeria preparations in the presence of macrophages accessory cells in a non-H-2-restricted manner. Considered collectively, these results suggest a potential mechanism by which gamma/delta T cells can predominate in epithelial tissues and at sites of infection.

PREVENTION OF GRAFT-VERSUS-HOST DISEASE FOLLOWING SMALL BOWEL TRANSPLANTATION WITH POLYCLONAL AND MONOCLONAL ANTILYMPHOCYTE SERUM

Graft-versus-host disease is a potential problem following small bowel transplantation. We have previously shown that a two-day intraperitoneal course of polyclonal antilymphocyte serum completely prevents GVHD without impairing allograft function in a unidirectional rat small bowel transplant model. In the present study we sought to determine the optimum route and timing of ALS administration and whether donor pretreatment with the anti-T cell receptor monoclonal antibody R73 would be similarly effective in preventing GVHD. Both intravenous and intraperitoneal injection of ALS effectively prevent GVHD in this model. ALS must be given to donors at least 48 hr prior to graft procurement for maximum effectiveness. Prevention of GVHD correlates with lymphocyte depletion in mesenteric lymph nodes, as opposed to peripheral blood or small bowel lamina propria. Donor pretreatment with the monoclonal antibody R73 significantly delays the onset of GVHD in this small bowel transplant model but appears less effective than polyclonal ALS.

Stimulation of human T cells via anti-T cell receptor monoclonal antibody BMA031: Distinct cellular events involving interleukin-2 receptor and lymphocyte function antigen 1

We have analyzed activation of resting human T cells by anti-T cell receptor (TCR) monoclonal antibody (mAb) BMA031, a murine mAb of the G2b isotype. Human peripheral blood lymphocytes (PBL) respond to anti-TCR mAb by short-term proliferation in vitro and by acquisition of responsiveness to interleukin 2 (rIL-2) in the absence of detectable IL-2 production. Cell depletion and limiting dilution experiments indicate that anti-TCR mAb ± rIL-2 stimulation covers a substantial portion of human T cells, including CD4 + and CD8 + cells. Enhancement by rIL-2 of anti-TCR mAb-induced proliferation is blocked by anti-IL-2 receptor (IL-2R, p55) mAb, while anti-TCR mAb-induced proliferation is not. In contrast, anti-TCR mAb-induced proliferation is blocked by anti-lymphocyte function antigen 1 (LFA-1, CD11a) mAb and is not demonstrable in PBL from two patients with severe congenital LFA-1 deficiency, not even in the presence of irradiated LFA-1 + PBL. We conclude that stimulation of resting human T cells by anti-TCR mAb BMA031 enables dissociation of distinct steps in T cell activation that specifically require participation of IL-2R (p55) and LFA-1 cell surface molecules in a mutually exclusive way.

The human interferon‐γ gene contains an inducible promoter that can be transactivated by tax I and II

T cells infected with the HTLV (human T cell leukemia virus)-I and -II retroviruses often express the lymphokine interferon-gamma (IFN-gamma). We sought the molecular explanation for this phenomena by co-transfecting the transactivator genes of these human retroviruses together with 5' flanking sequences of the human IFN-gamma gene linked to a heterologous reporter gene. In the presence of phytohemagglutinin or anti-T cell receptor monoclonal antibodies and phorbol 12-myristate 13-acetate, the IFN-gamma promoter is activated in human T cells, which can be further enhanced by co-transfection of the tax I or II genes. Using Bal-31 deletion analysis, we have found that induction by mitogens can be mapped to a region between -284 to -260 (bp) 5' of the transcriptional start site, which is separable from the sequence(s) further upstream which transmit the synergistic transactivation by tax I or II.

T cell receptors in autoimmune disease as targets for immune intervention

The optimal form of treatment for an autoimmune disease should be highly specific, have few side effects, and allow treatment of clinically apparent disease. One target that could fulfill these requirements is the T cell receptor. To answer the question whether treatment of autoimmune disease is possible with anti-T cell receptor antibodies, the heterogeneity of T cell receptor elements utilized in the T cell mediated autoimmune disease experimental allergic encephalomyelitis was analyzed. The limited heterogeneity of these elements allowed prevention and treatment of clinical autoimmune disease with anti-T cell receptor monoclonal antibodies. These results and their potential value for other autoimmune diseases are discussed.