Strength symmetry after autograft anterior cruciate ligament reconstruction.

OBJECTIVE: To compare postoperative isometric quadriceps strength indices (QI%) and hamstring strength limb symmetry indices (HI%) between partial thickness quadriceps tendon (pQT), full thickness quadriceps tendon (fQT), and bone-patellar-tendon bone (BPTB) autograft anterior cruciate ligament reconstruction (ACLR). METHODS: Patients with primary ACLR with pQT, fQT, or BPTB autograft with the documentation of quantitative postoperative strength assessments between 2016 and 2021 were included. Isometric Biodex data, including QI% and HI% (calculated as the percentage of involved to uninvolved limb strength) were collected between 5 and 8 months and between 9 and 15 months postoperatively. RESULTS: In total, 124 and 51 patients had 5-8- and 9-15-month follow-up strength data, respectively. No significant difference was detected between groups for sex. However, patients undergoing fQT were found to be older than those undergoing BPTB (24.6±7 vs 20.2±5; â€‹p = 0.01). There were no significant differences in the number of concomitant meniscus repairs between the groups (pQT vs. fQT vs. BPTB). No significant differences were detected in median (min-max) QI% between pQT, fQT, and BPTB 5-8 months [87 â€‹% (44%-130 â€‹%), 84 â€‹% (44%-110 â€‹%), 82 â€‹% (37%-110 â€‹%) or 9-15 months [89 â€‹% (50%-110 â€‹%), 89 â€‹% (67%-110 â€‹%), and 90 â€‹% (74%-140 â€‹%)] postoperatively. Similarly, no differences were detected in median HI% between the groups 5-8 months or 9-15 months postoperatively. CONCLUSION: The study was unable to detect differences in the recovery of quadriceps strength between patients undergoing ACLR with pQT, fQT, and BPTB autografts at 5-8 months and 9-15-months postoperatively. LEVEL OF EVIDENCE: III.

Patellar Tendon Load Progression during Rehabilitation Exercises: Implications for the Treatment of Patellar Tendon Injuries.

PURPOSE: This study aimed to evaluate patellar tendon loading profiles (loading index, based on loading peak, loading impulse, and loading rate) of rehabilitation exercises to develop clinical guidelines to incrementally increase the rate and magnitude of patellar tendon loading during rehabilitation. METHODS: Twenty healthy adults (10 females/10 males, 25.9 ± 5.7 yr) performed 35 rehabilitation exercises, including different variations of squats, lunge, jumps, hops, landings, running, and sports specific tasks. Kinematic and kinetic data were collected, and a patellar tendon loading index was determined for each exercise using a weighted sum of loading peak, loading rate, and cumulative loading impulse. Then the exercises were ranked, according to the loading index, into tier 1 (loading index ≤0.33), tier 2 (0.33 < loading index <0.66), and tier 3 (loading index ≥0.66). RESULTS: The single-leg decline squat showed the highest loading index (0.747). Other tier 3 exercises included single-leg forward hop (0.666), single-leg countermovement jump (0.711), and running cut (0.725). The Spanish squat was categorized as a tier 2 exercise (0.563), as was running (0.612), double-leg countermovement jump (0.610), single-leg drop vertical jump (0.599), single-leg full squat (0.580), double-leg drop vertical jump (0.563), lunge (0.471), double-leg full squat (0.428), single-leg 60° squat (0.411), and Bulgarian squat (0.406). Tier 1 exercises included 20 cm step up (0.187), 20 cm step down (0.288), 30 cm step up (0.321), and double-leg 60° squat (0.224). CONCLUSIONS: Three patellar tendon loading tiers were established based on a combination of loading peak, loading impulse, and loading rate. Clinicians may use these loading tiers as a guide to progressively increase patellar tendon loading during the rehabilitation of patients with patellar tendon disorders and after anterior cruciate ligament reconstruction using the bone-patellar tendon-bone graft.

Near complete quadriceps tendon healing 2 years following harvest in anterior cruciate ligament reconstruction.

PURPOSE: Despite the recent increase in the use of quadriceps tendon (QT) autograft in anterior cruciate ligament reconstruction (ACLR); however, there remains a paucity of literature evaluating the postoperative morphology of the QT. The present study aimed to determine the postoperative morphologic change of the QT at a minimum of 2 years following harvesting during ACLR. METHODS: Patients who underwent ACLR with QT autograft and underwent magnetic resonance imaging (MRI) at a minimum of 2 years following harvesting were retrospectively included in the study. The anterior-to-posterior (A-P) thickness, medial-to-lateral (M-L) width, cross-sectional area (CSA), and signal/noise quotient (SNQ) of the QT were assessed at 5 mm, 15 mm, and 30 mm proximal to the superior pole of the patella on MRI. The CSA was adjusted by the angle between the QT and the plane of the axial cut based on a cosine function (adjusted CSA). The A-P thickness, M-L width, adjusted CSA, and SNQ were compared pre- and postoperatively. In addition, defects or scar tissue formation in the harvest site were investigated on postoperative MRI. RESULTS: Thirty patients were recruited for the study. The mean duration between postoperative MRI and surgery was 2.8 ± 1.1 years. The mean A-P thickness was 10.3% and 11.9% larger postoperatively at 5 mm and 15 mm, respectively. The mean M-L width was 7.3% and 6.5% smaller postoperatively at 5 mm and 15 mm, respectively. There were no significant differences in the adjusted CSA between pre- and post-operative states (275.7 ± 71.6 mm2 vs. 286.7 ± 91.8 mm2, n.s.). There was no significant difference in the postoperative change in the SNQ of the QT at all assessment locations. Defect or scar tissue formation at the harvest site was observed in 4 cases (13.3%), and 5 cases (16.6%), respectively. CONCLUSION: At a minimum of 2 years following QT harvest during ACLR, the QT became slightly thicker and narrower (approximately 11% and 7%, respectively). While the current study demonstrates that QT re-harvesting can be considered due to nearly normalized tendon morphology, future histological and biomechanical studies are required to determine the re-harvesting potential of the QT. LEVEL OF EVIDENCE: IV.

Failure Rates and Complications After Multiple-Revision ACL Reconstruction: Comparison of the Over-the-Top and Transportal Drilling Techniques.

Background: Multiple-revision anterior cruciate ligament reconstruction (ACLR) presents several technical challenges, often due to residual hardware, tunnel widening, malposition, or staged surgeries. Purpose: To compare failure and complication rates between the over-the-top (OTT) and transportal drilling (TD) techniques in patients undergoing surgery for failed revision ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: The medical records of patients with at least 2 revision ACLRs using either the OTT or TD technique were reviewed retrospectively. Data on patient demographics, graft characteristics, number of revisions, concomitant procedures, complications, and failures were collected. Between-group comparisons of continuous and categorical variables were conducted with the independent-samples t test and the Fisher exact or chi-square test, respectively. Results: A total of 101 patients undergoing multiple-revision ACLR with OTT (n = 37, 37%) and TD (n = 64, 63%) techniques were included for analysis. The mean follow-up time was 60 months (range, 12-196 months). There were no significant differences in age, sex, body mass index, laterality, or follow-up length between groups (P > .05). Allograft was the graft used most frequently (n = 64; 67.3%) with no significant differences between groups in graft diameter (P > .05). There were no statistically significant differences between groups regarding rate of concurrent medial and lateral meniscus, cartilage, or lateral extra-articular procedures (P > .05). There was also no significant66 between-group difference in complication rate (OTT: n = 2 [5.4%]; TD: n = 8 [13%]) or graft failure rate (OTT: n = 4 [11%]; TD: n = 14 [22%]) (P > .05 for both). Conclusion: The results of this study showed notably high failure and complication rates in challenging multiple-revision ACLR. Complication and failure rates were similar between techniques, demonstrating that the OTT technique is a valuable alternative that can be used in a revision ACLR, particularly as a single-stage approach when the single-stage TD technique is not possible.

Reliability of Continuous Shear Wave Elastography in the Pathological Patellar Tendon.

OBJECTIVES: Patellar tendon injuries occur via various mechanisms such as overuse, or due to surgical graft harvest for anterior cruciate ligament reconstruction (ACLR). Quantified patellar tendon stiffness after injury may help guide clinical care. Continuous shear wave elastography (cSWE) allows for the assessment of viscosity and shear modulus in tendons. The reliability of the measure, however, has not been established in the patellar tendon. The purpose of this study was to investigate the interrater reliability, intrarater reliability, and between-day stability of cSWE in both healthy and pathological patellar tendons. METHODS: Participants with patellar tendinopathy (n = 13), history of ACLR using bone-patellar tendon-bone autograft (n = 9), and with no history of patellar tendon injury (n = 13) were recruited. cSWE was performed 4 times by multiple raters over 2 days. Intraclass correlations (ICC) and minimum detectable change (MDC95% ) were calculated. RESULTS: Good to excellent between-day stability were found for viscosity (ICC = 0.905, MDC95%  = 8.3 Pa seconds) and shear modulus (ICC = 0.805, MDC95%  = 27.4 kPa). The interrater reliability measures, however, were not as reliable (ICC = 0.591 and 0.532). CONCLUSIONS: cSWE is a reliable assessment tool for quantifying patellar tendon viscoelastic properties over time. It is recommended, however, that a single rater performs the measure as the interrater reliability was less than ideal.

Relationships between tendon structure and clinical impairments in patients with patellar tendinopathy.

The clinical relevance of altered tendon structure in patellar tendinopathy is contested since structural change persists after symptom resolution. The purpose of this study was to explore the relationships between tendon structure and clinical impairments in patellar tendinopathy. In this retrospective, secondary analysis of individuals with patellar tendinopathy (n = 41), tendon structure (thickness, cross-sectional area [CSA], shear modulus, and viscosity), symptom severity, lower extremity function (counter-movement jump [CMJ] height), and quadriceps muscle performance (knee extension force and central activation ratio [CAR]) were recorded for the symptomatic limb. Relationships among structure, symptom severity, lower extremity function, and quadriceps muscle performance were examined using sequential regression models. Adjusting for age, sex, body mass index, and pain levels, there were significant positive relationships for thickness (p < 0.001, ß = 0.718) and viscosity (p = 0.006, ß = 0.496) with CMJ height. There were significant negative relationships between CSA with both CMJ height (p = 0.001, ß = -0.538) and CAR (p = 0.04, ß = -0.517). This is the first study to demonstrate relationships between tendon structure and lower extremity function or quadriceps muscle performance in patients with patellar tendinopathy. Clinical significance: Since structural changes persist after symptom resolution, addressing these changes may assist in restoring lower extremity function and quadriceps muscle performance.

Pain-guided activity modification during treatment for patellar tendinopathy: a feasibility and pilot randomized clinical trial.

BACKGROUND: Activity modification is a key component of patellar tendinopathy treatment but there is a lack of evidence guiding activity modification prescription. Use of activity modification in treatment studies has varied widely and the impact of those recommendations has not been directly investigated or compared. The purpose of this study was to assess (1) the feasibility of using pain-guided activity modification during treatment for patellar tendinopathy and (2) if our outcome measures are responsive to changes in tendon health over the course of treatment. METHODS: This was an unblinded, randomized two-arm pilot and feasibility study randomized clinical trial with parallel assignment, conducted in Newark, DE. Individuals between the ages of 16 and 40 years old with patellar tendinopathy were included. Participants were randomly assigned to a pain-guided activity (PGA) or pain-free activity (PFA) group using a spreadsheet-based randomization scheme. All participants received standardized treatment using a modified version of the heavy-slow resistance protocol 3×/week for 12 weeks. For the first 6 weeks, the PGA group used the Pain-Monitoring Model to guide activity outside of treatment and the PFA group was restricted from running, jumping, or activities that provoked their patellar tendon pain. Feasibility outcomes included recruitment, enrollment, randomization, compliance, and retention percentages. Clinical evaluations were conducted at baseline, 6, and 12 weeks to assess symptom severity, psychological factors, tendon morphology and mechanical properties, lower extremity function, and quadriceps muscle performance. RESULTS: In a ~ 13-month period, 108 individuals were screened, 47/108 (43.5%) were eligible for participation, and 15/47 (32.0%) of those were enrolled (9 PGA, 6 PFA). The recruitment rate was 1.15 participants/month. The mean ± SD compliance with treatment was PGA: 86.1 ± 13.0% and PFA: 67.1 ± 30.7%. There was one missed evaluation session and two adverse events, which were not due to study interventions. Changes exceeding the smallest detectable change were observed for at least one outcome in each domain of tendon health. CONCLUSIONS: Use of pain-guided activity modification during exercise therapy for patellar tendinopathy was found to be feasible, and the proposed outcome measures appropriate. Computer-based allocation concealment, blinding of evaluators, and greater recruitment of high-level athletes should be implemented in future trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03694730 . Registered 3rd of October, 2018.

Relationship between mechanical properties (shear modulus and viscosity), age, and sex in uninjured Achilles tendons.

Tendon mechanical properties have been proposed as a biomarker of tendon health to track response to injury and treatment. Prior to utilizing these properties in an injured population, it is critical to understand how these are influenced by age and sex in an uninjured population. A retrospective analysis was conducted of 118 uninjured Achilles tendons to evaluate the relationship between tendon mechanical properties, age and sex. Mechanical properties (shear modulus and viscosity) were assessed using continuous shear wave elastography. A moderator regression analysis was completed to examine the relationship between tendon mechanical properties, age and sex, after adjusting for body mass index and physical activity level. There was an interaction between age and sex for shear modulus (p=0.049, R2 change=0.034). Females had a negative relationship between age and shear modulus (p=0.030, ß=-0.350) but no relationship was observed for males (p=0.78, ß=0.031). A positive relationship was found between age and viscosity (p=0.034, ß=0.214). Increased viscosity was related to increased age with no difference between sexes. The effect of aging on shear modulus differed between men and women and may help explain sex specific injury risks and their differing response to mechanical load.

Current Clinical Concepts: Conservative Management of Achilles Tendinopathy.

Achilles tendinopathy is a painful overuse injury that is extremely common in athletes, especially those who participate in running and jumping sports. In addition to pain, Achilles tendinopathy is accompanied by alterations in the tendon's structure and mechanical properties, altered lower extremity function, and fear of movement. Cumulatively, these impairments limit sport participation and performance. A thorough evaluation and comprehensive treatment plan, centered on progressive tendon loading, is required to ensure full recovery of tendon health and to minimize the risk of reinjury. In this review, we will provide an update on the evidence-based evaluation, outcome assessment, treatment, and return-to-sport planning for Achilles tendinopathy. Furthermore, we will provide the strength of evidence for these recommendations using the Strength of Recommendation Taxonomy system.

Distinguishing Quadriceps Tendinopathy and Patellar Tendinopathy: Semantics or Significant?

Jumper's knee is not synonymous with patellar tendinopathy. The term includes patellar tendinopathy and quadriceps tendinopathy. Although the patellar and quadriceps tendons work in tandem as part of the extensor mechanism of the knee, they have distinct anatomy and functional roles. As a result, there are probable differences in risk factors, etiology, and response to treatment. It is time to clinically separate patellar tendinopathy and quadriceps tendinopathy and design more specific rehabilitation programs. In this Viewpoint, the authors will (1) provide a rationale for distinguishing the 2 clinical entities-patellar tendinopathy and quadriceps tendinopathy-for treatment decision making, and (2) identify areas of research priority in quadriceps tendinopathy. J Orthop Sports Phys Ther 2019;49(9):627-630. doi:10.2519/jospt.2019.0611.

Investigational RNAi Therapeutic Targeting C5 Is Efficacious in Pre-clinical Models of Myasthenia Gravis.

Complement-mediated damage to the neuromuscular junction (NMJ) is a key mechanism of pathology in myasthenia gravis (MG), and therapeutics inhibiting complement have shown evidence of efficacy in the treatment of MG. In this study, we describe the development of a subcutaneously administered N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C5 component of complement that silences C5 expression in the liver (ALN-CC5). Treatment of wild-type rodents with ALN-CC5 resulted in robust and durable suppression of liver C5 expression. Dose-dependent serum C5 suppression was observed in non-human primates, with a lowering of serum C5 of up to 97.5% and the concomitant inhibition of serum complement activity. C5 silencing was efficacious in ameliorating disease symptoms in two standard rat models of MG, demonstrating the key role of circulating C5 in pathology at the NMJ. Improvement in disease activity scores and NMJ pathology was observed at intermediate levels of complement activity inhibition, suggesting that complete ablation of complement activity may not be required for efficacy in MG. The pre-clinical studies of ALN-CC5 and efficacy of C5 silencing in rat models of MG support further clinical development of ALN-CC5 as a potential therapeutic for the treatment of MG and other complement-mediated disorders.

Modifiable risk factors for patellar tendinopathy in athletes: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis identifying (1) potential modifiable risk factors and (2) associated modifiable factors for patellar tendinopathy in athletes. DESIGN: A systematic review and meta-analysis was conducted. Risk of bias was assessed using the Newcastle-Ottawa Scale and grouped based on study design. Meta-analytic statistics were performed for items reported by five or more studies. A strength of evidence rating is provided for items not appropriate for meta-analysis. DATA SOURCES: PubMed, Web of Science, Scopus and Cinahl were searched on 14 November 2017. ELIGIBILITY CRITERIA: Quantitative, original research reporting potential modifiable risk factors or associated factors, comparing athletes with patellar tendinopathy with a group without the injury. RESULTS: 862 records were screened and 31 articles were included (6 prospective, 25 cross-sectional). There was a lack of strong evidence for any potential modifiable risk factor or associated factors. There was limited or conflicting evidence that decreased ankle dorsiflexion range of motion, decreased posterior thigh and quadriceps flexibility, greater volume of jump training, more volleyball sets played per week, greater countermovement jump (CMJ) height and greater activity volume are potential modifiable risk factors. Meta-analysis supported greater activity volume (Cohen's d=0.22, 95% CI 0.06 to 0.39, p=0.008), higher body weight (0.36, 0.17 to 0.55, p<0.001) and greater CMJ height (0.31, 0.07 to 0.56, p=0.01) as associated modifiable factors. CONCLUSIONS: There is a lack of strong evidence for any potential modifiable risk factors or associated factors. Factors with lower levels of support may be of interest in designing prevention programmes but require further research in high-quality, prospective studies.

Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles.

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4(+) T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4(+) T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4(+) T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4(+) T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4(+) T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs' efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases.

RNA inhibition highlights cyclin D1 as a potential therapeutic target for mantle cell lymphoma.

Mantle cell lymphoma is characterized by a genetic translocation results in aberrant overexpression of the CCND1 gene, which encodes cyclin D1. This protein functions as a regulator of the cell cycle progression, hence is considered to play an important role in the pathogenesis of the disease. In this study, we used RNA interference strategies to examine whether cyclin D1 might serve as a therapeutic target for mantle cell lymphoma. Knocking down cyclin D1 resulted in significant growth retardation, cell cycle arrest, and most importantly, induction of apoptosis. These results mark cyclin D1 as a target for mantle cell lymphoma and emphasize the therapeutic potential hidden in its silencing.

Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.

Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic LNPs (cLNPs). The role of apoE was investigated using both in vitro studies employing recombinant apoE and in vivo studies in wild-type and apoE(-/-) mice. Receptor dependence was explored in vitro and in vivo using low-density lipoprotein receptor (LDLR(-/-))-deficient mice. As an alternative to endogenous apoE-based targeting, we developed a targeting approach using an exogenous ligand containing a multivalent N-acetylgalactosamine (GalNAc)-cluster, which binds with high affinity to the asialoglycoprotein receptor (ASGPR) expressed on hepatocytes. Both apoE-based endogenous and GalNAc-based exogenous targeting appear to be highly effective strategies for the delivery of iLNPs to liver.

Drug delivery-mediated control of RNA immunostimulation.

RNA interference (RNAi) has generated significant interest as a strategy to suppress viral infection, but in some cases antiviral activity of unmodified short-interfering RNA (siRNA) has been attributed to activation of innate immune responses. We hypothesized that immunostimulation by unmodified siRNA could mediate both RNAi as well as innate immune stimulation depending on the mode of drug delivery. We investigated the potential of immunostimulatory RNAs (isRNAs) to suppress influenza A virus in vivo in the mouse lung. Lipidoid 98N12-5(1) formulated with unmodified siRNA targeting the influenza nucleoprotein gene exhibited antiviral activity. Formulations were optimized to increase antiviral activity, but the antiviral activity of lipidoid-delivered siRNA did not depend on sequence homology to the influenza genome as siRNA directed against unrelated targets also suppressed influenza replication in vivo. This activity was primarily attributed to enhancement of innate immune stimulation by lipidoid-mediated delivery, which indicates increased toll-like receptor (TLR) activation by siRNA. Certain chemical modifications to the siRNA backbone, which block TLR7/8 activation but retain in vitro RNAi activity, prevented siRNA-mediated antiviral activity despite enhanced lipidoid-mediated delivery. Here, we demonstrate that innate immune activation caused by unmodified siRNA can have therapeutically relevant effects, and that these non-RNAi effects can be controlled through chemical modifications and drug delivery.

Genetic deletion or antibody blockade of alpha1beta1 integrin induces a stable plaque phenotype in ApoE-/- mice.

OBJECTIVE: Adhesive interactions between cells and the extracellular matrix play an important role in inflammatory diseases like atherosclerosis. We investigated the role of the collagen-binding integrin alpha1beta1 in atherosclerosis. METHODS AND RESULTS: ApoE-/- mice were alpha1-deficient or received early or delayed anti-alpha1 antibody treatment. Deficiency in alpha1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, alpha1-deficient mice had a reduced macrophage and CD3+ cell content, collagen and smooth muscle cell content increased, lipid core sizes decreased, and cartilaginous metaplasia occurred. Anti-alpha1 antibody treatment reduced the macrophage content in initial plaques after early and delayed treatment, decreased the CD3+ cell content in advanced plaques after delayed treatment, and increased the collagen content in initial and advanced plaques after delayed treatment. Migration assays performed on alpha1-deficient macrophages on collagen I and IV substrata revealed that alpha1-deficient cells can migrate on collagen I, but not IV. Anti-alpha1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV. CONCLUSIONS: Our results suggest that alpha1beta1 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions by adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a stable plaque phenotype.

The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection.

A common feature of many infections is that many pathogen-specific memory T cells become established in diverse nonlymphoid tissues. A mechanism that promotes the retention and survival of the memory T cells in diverse tissues has not been described. Our studies show that the collagen binding alpha1beta1 integrin, VLA-1, is expressed by the majority of influenza-specific CD8 T cells recovered from nonlymphoid tissues during both the acute and memory phases of the response. Antibody treatment or genetic deficiency of VLA-1 decreased virus-specific CTL in the lung and other nonlymphoid tissues, and increased them in the spleen. In spite of the increase in the spleen, secondary heterosubtypic immunity against flu was compromised. This suggests that VLA-1 is responsible for retaining protective memory CD8 T cells in the lung and other tissues via attachment to the extracellular matrix.

Expression and functional importance of collagen-binding integrins, alpha 1 beta 1 and alpha 2 beta 1, on virus-activated T cells.

Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated T cells, that expression of alpha(1)beta(1) remains elevated on memory T cells, and that expression of alpha(1)beta(1) parallels that of viral-specific effector CD8(+) T cells (defined by tetramer and IFN-gamma staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of alpha(1)-deficient activated/memory T cells. Thus, expression of alpha(1)beta(1) and alpha(2)beta(1) integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of alpha(1)beta(1) blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues.

A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis.

A lymphotoxin-beta (LTbeta) receptor-Ig fusion protein (LTbetaR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTbetaR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTbetaR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTbetaR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.