anti-CD11a Monoclonal Antibody Research Articles

Cytokine-targeted treatment in alopecia areata - new possibilities?

Alopecia areata is a form of non-scarring hair loss characterised by a recurrent and difficult-to-treat course. The aetiology of this disease is still incompletely understood. However, multiple immunological pathways and an abnormal cytokine profile in patients with alopecia areata have been described. There are many therapeutic options for patients with alopecia areata, including topical, intralesional or systemic corticosteroids, contact immunotherapy, phototherapy and non-corticosteroid immunosuppressive drugs such as cyclosporine, methotrexate or azathioprine. However, these treatments have limited efficacy and may be associated with side effects. In addition, Janus kinase inhibitors have been shown to cause metabolic disorders. Therefore, their use in patients with alopecia areata may be limited. Other cytokine-targeted therapies have been shown to be effective in alopecia areata, such as apremilast (a phosphodiesterase 4 inhibitor), ustekinumab (a human immunoglobulin (Ig) G1 kappa monoclonal antibody directed against interleukin 12 and 23), abatacept (a soluble fusion protein which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 to the modified Fc portion of human immunoglobulin G1), secukinumab (an IL-17A antagonist) and dupilumab (a monoclonal antibody that blocks interleukin 4 and interleukin 13). TNF inhibitors (such as infliximab, adalimumab and etanercept) have been described to be ineffective in alopecia areata. In addition, disease exacerbation after TNF therapy has been reported. Alefacept (an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding part of human leukocyte function antigen-3 fused to the Fc part of human IgG1) and efalizumab (anti-CD11a monoclonal antibody) have not shown efficacy in alopecia areata. There are also isolated reports of alopecia areata after therapy with omalizumab (recombinant humanised monoclonal antibody anti-IgE), ixekizumab (inhibitor of IL-17A) and brodalumab (inhibitor of IL-17R).

Tolerability, pharmacokinetics and pharmacodynamics of CMAB001, an anti-CD11a antibody, in Chinese healthy volunteers and psoriatic patients

To evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and primary tolerability of an anti-CD11a monoclonal antibody (CMAB001) in Chinese healthy volunteers and psoriatic patients. Two open-label studies were conducted. One was a parallel-group, single-center, dose-escalation test, including 24 healthy adult volunteers from 18 to 45 years in age. All subjects randomly received a single subcutaneous injection dose of 0.5, 1.0 or 2.0 mg/kg. The other was a multiple-dose study: 10 adult psoriatic patients were administered weekly subcutaneous injections of 1.0 mg/kg for 7 weeks. CMAB001 was well tolerated in the single- and multiple-dose studies. Slow absorption was observed in both studies. In the single-dose study, the concentration of CMAB001 reached its highest level 2 d later after the injection, and the C(max) increased in an approximate dose-proportionate manner, while the area under curve (AUC) showed much greater than dose-proportionate increase. In the multiple-dose study, the steady-state serum concentration level was attained following the 4th injection. CMAB001 exhibited a nonlinear pharmacokinetic profile over the dose range from 0.5 to 2.0 mg/kg, and was well tolerated in healthy volunteers and psoriatic patients.

LFA-1 Expression in a Series of Colorectal Adenocarcinomas

LFA-1 is an adhesion molecule which belongs to the β2-integrin family. Overexpression of LFA-1 in hepatic natural killer cells has been associated with increased apoptosis of neoplastic cells in colorectal cancer (CRC); moreover, studies in CRC have linked LFA-1 overexpression in neoplastic cells with vascular intrusion through adhesion to endothelial cells, thus implying a possible role in creation of metastases. We studied the expression of LFA-1 in a series of 82 patients with CRC. A standard three-step immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue sections. An IgG2a anti-CD11a monoclonal antibody was used. Cases were characterized according to clinicopathological variables including sex, age, tumor localization, size, grade, Dukes stage, wall invasion, and presence of metastatic lymph nodes (mLNs) or distal metastases. LFA-1 was expressed at the primary tumor site in 51 cases and 6/33 cases with metastatic lymphnodes. In Dukes D cases (n = 4), only one case was LFA-1(+). LFA-1 expression at the primary tumor site was associated with the absence of metastatic disease and with Dukes B stage. However, in those cases with LFA-1 expression in cancer cells in mLNs, this was associated with its expression at the primary tumor site. The positive association of LFA-1 expression in mLNs when the primary tumor site is also LFA-1(+) could imply an adaptation advantage of this specific cellular clone to its micro-environment, predisposing it to creation of mLNs, pointing to a role for LFA-1 in creation of mLNs in CRC.

Molecular and virulence characteristics of an outer membrane-associated RTX exoprotein in Pasteurella pneumotropica

BackgroundPasteurella pneumotropica is a ubiquitous bacterium that is frequently isolated from laboratory rodents and causes various clinical symptoms in immunodeficient animals. Currently two RTX toxins, PnxIA and PnxIIA, which are similar to hemolysin-like high-molecular-weight exoproteins are known in this species. In this study, we identified and analyzed a further RTX toxin named PnxIIIA and the corresponding type I secretion system.ResultsThe RTX exoprotein, PnxIIIA, contains only a few copies of the RTX repeat-like sequence and 3 large repeat sequences that are partially similar to the outer membrane protein found in several prokaryotes. Recombinant PnxIIIA protein (rPnxIIIA) was cytotoxic toward J774A.1 mouse macrophage cells, whereas cytotoxicity was attenuated by the addition of anti-CD11a monoclonal antibody. rPnxIIIA could bind to extracellular matrices (ECMs) and cause hemagglutination of sheep erythrocytes. Binding was dependent on the 3 large repeat sequences in PnxIIIA. Protein interaction analyses indicated that PnxIIIA is mainly localized in the outer membrane of P. pneumotropica ATCC 35149 in a self-assembled oligomeric form. PnxIIIA is less cytotoxic to J774A.1 cells than PnxIA and PnxIIA.ConclusionsThe results implicate that PnxIIIA is located on the cell surface and participates in adhesion to ECMs and enhanced hemagglutination in the rodent pathogen P. pneumotropica.

Efalizumab for severe palmo‐plantar psoriasis: an open‐label pilot trial in five patients

Palmo-plantar psoriasis (PPP) is a disabling condition that significantly impairs quality of life. PPP tends to be resistant to conventional therapies and may last for several years. Topical treatments are usually ineffective. Systemic therapy with oral retinoids and psoralen plus ultraviolet A is frequently required, although it rarely leads to remission. We conducted an open-label, pilot study to evaluate treatment of PPP with efalizumab, an anti-CD11a monoclonal antibody approved for the treatment of chronic, refractory moderate to severe plaque psoriasis in adults. Five patients with severe PPP received efalizumab treatment for 24 weeks. All five patients responded favourably by week 12 and showed further improvement at week 24 of uninterrupted therapy. Mean physician-assessed severity scores and patient-reported outcome scores improved almost 75% after 12 weeks and 90% after 24 weeks. At week 32, three patients maintained the response seen at week 24, while two patients suspended efalizumab. Efalizumab therapy was well tolerated and effective in five patients with severe PPP, allowing a significant improvement in quality of life.

New-Onset Ulcerative Colitis in a Patient Treated With the Anti-CD11a Monoclonal Antibody Efalizumab

1Department of Gastroenterology, Royal College of Surgeons, Beaumont Hospital, Dublin, Ireland. Correspondence: Garret Cullen, MD, Department of Gastroenterology, Royal College of Surgeons, Beaumont Hospital, Dublin 9, Ireland. published online 3 March 2009 E-mail: [email protected]

Delayed autoimmune hemolytic anemia in efalizumab-treated psoriasis

Efalizumab, a humanized anti-CD11a monoclonal antibody, has been shown to treat plaque psoriasis. A known association between this drug and autoimmune thrombocytopenia has already been established. More recently publicized, however, is efalizumab's ability to affect another cell line--that of the erythrocyte--and cause an autoimmune hemolytic anemia that typically occurs 4 to 6 months after initiating therapy. In this article, we report the case of a patient who developed autoimmune hemolytic anemia after 8 months of successful treatment with efalizumab. His delayed presentation suggests that monitoring of blood cell counts longer than 6 months may be warranted.

Efalizumab-Associated Papular Psoriasis

Efalizumab is a human anti-CD11a monoclonal antibody used in the treatment of patients with moderate to severe plaque psoriasis. Some of the patients develop new papular lesions during treatment, which are predominantly located in the flexural regions. Four patients with recalcitrant psoriasis undergoing treatment with efalizumab presented with erythematous, partly scaly papules and small plaques on previously unaffected areas after 4 to 10 weeks of efalizumab therapy. Tissue sections of biopsy specimens were stained with hematoxylin-eosin, and immunohistochemical staining was performed using monoclonal antibodies against CD3, CD4, CD8, T-cell-restricted intracellular antigen 1, granzyme B, neutrophil elastase, CD68, CD1a, CD11c, HLA-DR, CD25, CD20, and CD56. Histopathological and immunohistochemical examination of the lesions showed features consistent with psoriasis and activation of various leukocyte subtypes including T cells, dendritic cells, macrophages, and neutrophils. Papular eruptions appearing during efalizumab therapy represent new psoriatic lesions and could be referred to as efalizumab-associated papular psoriasis (EAPP). They usually do not necessitate termination of efalizumab therapy and may optionally be treated with topical corticosteroids. Dermatologists should be aware of these lesions and inform their patients accordingly.

Long-term treatment of plaque psoriasis with efalizumab: an Italian experience

Biologic agents are an important new class of drugs, offering targeted treatment for chronic skin diseases such as psoriasis. The biologic therapy efalizumab is an anti-CD11a monoclonal antibody, which was approved by the European regulatory agency in 2004 for the treatment of moderate-to-severe plaque psoriasis. Here we describe our 2-year experience in treating over 100 patients with moderate-to-severe psoriasis with efalizumab at two dermatology centres in Italy. Overall, we found efalizumab is efficacious for a large subset of patients, regardless of previous therapies received, and has an easily manageable safety profile. We believe one important quality of efalizumab is the stability and maintenance of clinical response over time. We found that most patients who respond to treatment experience a long-term clearing of psoriasis with only mild recurrence events. Our experience with individual cases provides specific insights into efalizumab re-treatment, the use of efalizumab in patients with a history of heart failure, and the management of patients who become pregnant or conceive while receiving efalizumab therapy. In summary, our off-trial experience in over 100 patients confirms the efficacy and safety of efalizumab in the treatment of moderate-to-severe plaque psoriasis.

Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity

Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.

Lymphocyte Function-Associated Antigen-1-Dependent Inhibition of Corneal Wound Healing

Abrasion of murine corneal epithelium induces neutrophil emigration through limbal vessels into the avascular corneal stroma, peaking within 12 to 18 hours after wounding. A central corneal wound closes within 24 hours by epithelial cell migration and division, and during wound closure corneal epithelial cells express intercellular adhesion molecule (ICAM)-1 (CD54). We investigated the contributions of lymphocyte function-associated antigen (LFA)-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) by analyzing wound closure in mice with targeted deletions of CD11a (CD11a-/-) or CD11b (CD11b-/-). In contrast to CD11a-/- mice, CD11b deficiency revealed a much greater delay in epithelial wound closure with >90% inhibition of epithelial cell division at a time when neutrophil accumulation in the cornea was approximately threefold higher than normal. Treating CD11b-/- mice with anti-CD11a monoclonal antibody at the time of epithelial abrasion resulted in significant reductions in neutrophils and significant increases in corneal epithelial cell division and migration. Treating CD11b-/- mice with anti-ICAM-1 significantly increased measures of healing but marginally reduced neutrophil influx. In conclusion, wound healing after corneal epithelial abrasion is disrupted by the absence of CD11b. The disruption is apparently linked to excessive neutrophil accumulation at a time when epithelial division is essential to wound repair, and neutrophils appear to be detrimental through processes involving LFA-1 and ICAM-1.

Efalizumab for psoriasis

Psoriasis is now recognized as the most prevalent T-cell-mediated inflammatory disease in humans. While there are a wide variety of therapies that are indicated for the management of psoriasis with different modes of action and different effects, currently, psoriasis is considered as an incurable disease. Biological agents interfere with specific components of the autoimmune response and offer a new therapeutic approach to psoriasis. Efalizumab is a recombinant, humanized immunoglobulin G1 anti-CD11a monoclonal antibody that has been developed for the potential treatment of plaque psoriasis. It has been demonstrated in Phase III clinical trials to have a rapid onset of clinical response and to control chronic moderate-to-severe plaque psoriasis over 1 year of treatment. It has also been reported to have a positive impact on patient quality of life.

Simvastatin regulates non-neuronal cholinergic activity in T lymphocytes via CD11a-mediated pathways

Lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. We previously showed that antithymocyte globulin stimulates an independent, non-neuronal cholinergic system in T cells via LFA-1-mediated pathways, as evidenced by increases in acetylcholine (ACh) synthesis and choline acetyltransferase (ChAT) mRNA expression. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 α chain), which leads to immunomodulation. In the present study, we investigated whether simvastatin modulates lymphocytic cholinergic activity in T cells. We found that anti-CD11a monoclonal antibody (mAb) increased ChAT activity, ACh synthesis and release, and expression of ChAT and M 5 muscarinic ACh receptor mRNA in MOLT-3 cells, a human leukemic T cell line. Simvastatin abolished these anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. These results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways, and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.

Pharmacokinetic–Pharmacodynamic–Efficacy Analysis of Efalizumab in Patients with Moderate to Severe Psoriasis

Efalizumab is a humanized anti-CD11a monoclonal antibody that demonstrated efficacy in the treatment of patients with psoriasis. The objective of this study was to perform a pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy (E) modeling analysis with intersubject variability assessment to increase our understanding of the interaction of efalizumab with CD11a on T cells and consequent reduction in severity of disease in psoriasis patients. A total of 6,329 samples from 240 patients in five Phase I and II clinical studies were used in the analysis. For the analysis, plasma efalizumab concentration was used as the PK measurement, the percent of predose CD11a was used as the PD measurement, and the psoriasis area and severity index was used as the measure of efficacy. A receptor-mediated PK/PD model was developed that describes the dynamic interaction of efalizumab binding with CD11a. In the efficacy model, the rate of psoriasis skin production is directly proportional to the amount of free surface CD11a on T cells, which is offset by the rate of skin healing. An additional CD11a-independent component to psoriasis skin production accounted for incomplete response to efalizumab therapy. A Monte Carlo parametric expectation maximization method implemented in the ADAPT II program was used to obtain the estimate of population parameters and inter- and intrasubject variability. The final model described the PK/PD/E data in psoriasis patients reasonably well. In addition, simulations using the final model suggested that efalizumab administered less frequently could possibly be more convenient with similar efficacy.

Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury

To inactivate chronically the beta2-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF(+/+) PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF(+/+) PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF(+/+) and Mac-1-deficient (Mac-1(-/-)) mice. Adhesion of both Mac-1(-/-) and NIF(+/+) PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF(+/+) PMNs but the blockade of CD11b function. CD11b inactivation in NIF(+/+) mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF(+/+) mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation.

Recent Developments in Management of Psoriatic Arthritis

Until recently, little attention has been paid to psoriatic arthritis, perhaps because the disease was thought to be mild and infrequent. However, it has become clear that the disease may be severe in a significant proportion of the patients and may be more prevalent than initially considered. Recent studies supported the increasing clinical evidence that disruption of specific immune interactions can improve psoriasis and its musculoskeletal manifestations. Agents being evaluated for the treatment of psoriasis and psoriatic arthritis include, TNF-α antagonists: infliximab and etanercept, an anti-CD11a monoclonal antibody, efalizumab, and a soluble LFA-3-IgG fusion protein, alefacept. However, in concordance with the advent of new and emerging therapies, similar development in the measures of the disease activity and severity is highly required. This article gives an overview of the new developments in clinical assessment and management of psoriasis and its associated musculoskeletal manifestation. With the understanding of the disease immunopathogenesis, this review will outline a new suggested algorithm for management of psoriasis in its different clinical forms incorporating the new biologic agents with the conventional modalities. Keywords: psoriasis, psoriatic arthritis, tnf, leflunomide, alefacept, efalizumab

Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody

Surrogate antibodies are a potential solution to the limited safety testing possible with humanized monoclonal antibodies with restricted species cross-reactivity. However, there are currently no defined criteria by which a potential surrogate antibody should be judged prior to its use in determining safety issues for the clinical agent. We propose that, potential surrogates should undergo rigorous evaluation to assess pharmacological and toxicological activities in comparison to the clinical agent. The current studies evaluated a chimeric mouse/rat anti-mouse CD11a monoclonal antibody (muM17) as a potential surrogate for efalizumab, a humanized anti-CD11a antibody in development for psoriasis. CD11a is a subunit of lymphocyte function associated antigen-1, an integrin involved in cell–cell interactions important to immune responses and inflammation. In vitro pharmacology studies included binding affinity to whole mouse blood and inhibitory activity of muM17 in a mixed lymphocyte response assay. In vivo pharmacology was examined using a delayed type hypersensitivity assay in female CD-1 mice. The toxicology evaluation included a murine tissue cross-reactivity study and in vivo multiple dose studies in female CD-1 mice which were administered muM17 (0.1–30 mg/kg) via subcutaneous injections once a week for 4 weeks. Clinical observations, body weight, clinical pathology, T cell CD11a expression, immunogenicity, toxicokinetics, and lymphoid organ histopathology were evaluated. Finally, since reproductive safety testing would be an important application of the proposed surrogate antibody, a pilot study in pregnant mice was conducted that demonstrated proportional transfer of muM17 into the fetus. These studies demonstrated that muM17 has pharmacological and toxicological activities similar to efalizumab. The selection of dose and regimen for GLP (Good Laboratory Practice) toxicology studies and extrapolation to clinical dose levels was based on pharmacodynamic activity (CD11a downmodulation on T cells).

The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody

Background: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. Methods: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. Results: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P = .002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P = .0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 ± 7.5 (placebo) and 10.9 ± 8.4 (0.3 mg/kg) (P < .0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P = .004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. Conclusions: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis. (J Am Acad Dermatol 2001;45:665-74.)

Lymphocyte function-associated antigen 1 is a receptor for Pasteurella haemolytica leukotoxin in bovine leukocytes.

Pasteurella (Mannheimia) haemolytica leukotoxin (Lkt) causes cell type- and species-specific effects in ruminant leukocytes. Recent studies indicate that P. haemolytica Lkt binds to bovine CD18, the common subunit of all beta2 integrins. We designed experiments with the following objectives: to identify which member of the beta2 integrins is a receptor for Lkt; to determine whether Lkt binding to the receptor is target cell (bovine leukocytes) specific; to define the relationships between Lkt binding to the receptor, calcium elevation, and cytolysis; and to determine whether a correlation exists between Lkt receptor expression and the magnitude of target cell cytolysis. We compared Lkt-induced cytolysis in neutrophils from control calves and from calves with bovine leukocyte adhesion deficiency (BLAD), because neutrophils from BLAD-homozygous calves exhibit reduced beta2 integrin expression. The results demonstrate for the first time that Lkt binds to bovine CD11a and CD18 (lymphocyte function-associated antigen 1 [LFA-1]). The binding was abolished by anti-CD11a or anti-CD18 monoclonal antibody (MAb). Lkt-induced calcium elevation in bovine alveolar macrophages (BAMs) was inhibited by anti-CD11a or anti-CD18 MAb (65 to 94% and 37 to 98%, respectively, at 5 and 50 Lkt units per ml; P < 0.05). Lkt-induced cytolysis in neutrophils and BAMs was also inhibited by anti-CD11a or anti-CD18 MAb in a concentration-dependent manner. Lkt bound to porcine LFA-1 but did not induce calcium elevation or cytolysis. In neutrophils from BLAD calves, Lkt-induced cytolysis was decreased by 44% compared to that of neutrophils from control calves (P < 0.05). These results indicate that LFA-1 is a Lkt receptor, Lkt binding to LFA-1 is not target cell specific, Lkt binding to bovine LFA-1 correlates with calcium elevation and cytolysis, and bovine LFA-1 expression correlates with the magnitude of Lkt-induced target cell cytolysis.

Human Follicular Dendritic Cells Remain Uninfected and Capture Human Immunodeficiency Virus Type 1 through CD54-CD11a Interaction

It has been reported that human immunodeficiency virus type 1 (HIV-1) bound to follicular dendritic cells (FDCs) remains highly infectious to CD4(+) T cells even when it forms immune complexes with neutralizing antibody (HIV-1/IC). To elucidate the role of FDCs in HIV-1 transmission to CD4(+) T cells in lymph nodes, we have isolated and purified FDCs from human tonsils and examined whether the HIV-1/IC trapped on their surface is infectious to CD4(+) T cells. To our surprise, not the HIV-1/IC but the antibody-free HIV-1 on FDCs could be transmitted to CD4(+) T cells. Furthermore, in contrast to previous studies showing that FDCs are productively infected with HIV-1, the present study clearly demonstrated that FDCs were not the target cells for HIV-1 infection. FDCs could capture the viral particles on their surface; however, the binding of HIV-1 to FDCs was strongly inhibited by the presence of anti-CD54 (ICAM-1) monoclonal antibody (MAb) and anti-CD11a (LFA-1) MAb, suggesting that the adhesion molecules play an important role in the interaction between HIV-1 and FDCs.