Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.

Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.

Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells.

CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7(-/-)) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7(-/-) T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7(-/-) T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7(-/-) T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7(-/-) T cells were capable of generating robust graft-versus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7(-/-) regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.

In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-alpha (TNF-alpha) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.

Healed cuff repairs impart normal shoulder scores in those 65 years of age and older.

BACKGROUND: It is unclear whether repaired rotator cuffs heal in older patients and whether the function in those shoulders compares with those of similarly aged patients with untreated tears. QUESTIONS/PURPOSE: We questioned whether, in patients 65 years of age and older, shoulders with rotator cuff repairs that remained intact would have Simple Shoulder Test (SST) scores and Constant scores similar to those of untreated individuals with intact rotator cuffs. METHODS: We retrospectively reviewed 39 patients (42 shoulders) 65 years of age and older in whom 42 full-thickness rotator cuff tears were repaired with a mini open technique. All patients completed SST and Constant scores 12 to 60 months postoperatively; all patients also had ultrasound at those times to assess the status of the repair. These findings were compared with 200 untreated similarly aged shoulders assessed in the same fashion. RESULTS: Shoulders with healed repairs (33 of 42) had similar mean SST scores and Constant scores to those in untreated shoulders with intact rotator cuffs. Those with healed repairs also had higher SST and Constant scores than those with unhealed repairs. Finally, shoulders with healed repairs had higher SST and Constant scores than those with untreated tears. CONCLUSIONS: When rotator cuffs healed the function was comparable to that of similarly-aged patients without tears and better than that of patients with untreated tears. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Arthroscopic Treatment of Osteochondral Lesions of the Talus in a Pediatric Population: A Minimum 2-Year Follow-up.

BACKGROUND: Treatment of osteochondral lesions of the talus (OLTs) in children presents a difficult clinical challenge, with few large series reported. PURPOSE: To evaluate functional and radiographic outcomes for children and adolescents undergoing arthroscopic treatment of symptomatic OLT with a minimum follow-up of 2 years. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients were identified who had symptomatic OLT treated arthroscopically with marrow stimulation techniques. Inclusion criteria were age ≤18 years, symptomatic chronic OLT as the surgical indication, failure of nonoperative treatment, and minimum follow-up of 24 months. Outcome measures included Foot Function Index, American Orthopaedic Foot and Ankle Society Hindfoot Score, Tegner Activity Scale, 36-Item Short Form Health Survey (Short Form-36, v 2), visual analog scale, ankle range of motion, and patient satisfaction survey. Weightbearing radiographs were compared with preoperative radiographs via an ankle arthritis classification system. Magnetic resonance imaging (MRI) was used to evaluate postoperative lesion characteristics per the MOCART scale (magnetic resonance observation of cartilage repair tissue). The size, location, lesion stability, traumatic etiology, skeletal maturity, and length of follow-up were recorded and analyzed through univariate logistic regression. RESULTS: The study group consisted of 22 patients (11 male, 11 female) with a mean age of 14.4 years (range, 8-18 years) and a mean follow-up of 8.3 years (range, 2-27 years). Of 22 patients, 20 were satisfied with the results from surgery and would recommend it to others. Mean follow-up visual analog scale for pain was reported as 2.2 on a 10-point scale, and mean American Orthopaedic Foot and Ankle Society score at follow-up was 86.6. Mean postoperative Foot Function Index scores for the study group were as follows: pain, 17.1; disability, 16.5; activity, 4.7; and overall, 38.7. Mean Short Form-36 physical component score was 50.7. Postoperative radiographs indicated a van Dijk osteoarthritis grade of 0 in 56%, I in 38%, II in 6%, and III in 0%. Postoperative MRI MOCART scores showed complete filling of the cartilage in 27% of cases, complete graft integration in 22%, and intact repair surface in 22%, with a mean MOCART score of 48.0. No correlation was found between radiographic and MRI findings and clinical outcomes. None of the prognostic factors were significantly associated with patient satisfaction, progression of arthritis, or MOCART scores. CONCLUSION: Arthroscopic treatment of symptomatic OLT in adolescent patients (≤18 years) demonstrated high functional outcomes, high clinical satisfaction rates, and minimal radiographic osteoarthritic progression despite low MOCART scores.

B-cell studies in chronic ethanol mice.

Chronic alcohol abuse leads to multiple defects in the immune system, leading to an increased risk of infectious disease and malignancy. Immune lesions encompass both the innate and adaptive arms and include deficiencies in the B-cell compartment. Long-term alcoholics exhibit loss of B cells in the periphery and diminished ability to generate protective antibodies. To better mimic the chronic alcoholic patient, our group has used an ethanol-in-drinking-water mouse model. Mice consuming alcohol in this manner progressively develop a range of immune abnormalities, including defects in humoral immunity. To document and explore B-cell lesions in ethanol-consuming mice, our laboratory has used a broad panel of technologies. These include protocols to define the physical state of B cells in the bone marrow and periphery, in vitro approaches to test B-cell activation potential and in vivo experiments to document the humoral competence of the host. These key techniques are detailed in the present chapter.

Complications in ankle and foot arthroscopy.

Arthroscopy has many potential complications, whether it is done in the ankle, shoulder, knee, or other joints. Foot and ankle arthroscopy has progressed significantly since its beginning by Burman in 1931. Over the past 2 decades, arthroscopy equipment and instrumentation has improved and newer techniques have been developed. A heightened interest in foot and ankle arthroscopy has grown as diagnostic and imaging capabilities have improved. As the number of arthroscopic procedures of the foot and ankle has increased, so has the opportunity for significant complications.

The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting.

Graft-versus-host disease (GVHD) remains a major barrier to the long-term success of allogeneic hematopoietic stem-cell transplantation for hematologic malignancies. This has prompted a great deal of interest in the development of alternative GVHD management strategies such as the adoptive transfer of lymphocytes with immunosuppressant activity. This review will focus on the biology of thymically derived regulatory T-cells (Tregs) and their potential therapeutic role in human bone marrow transplantation. A discussion of their basic suppressive mechanisms and in vivo trafficking patterns will be presented, along with an overview of important preclinical studies using murine GVHD/tumor models. Currently available clinical data will also be discussed, including the contribution of Tregs to various transplant outcome parameters such as GVHD incidence and malignancy relapse rates.