Patient-individualized CD8⁺ cytolytic T-cell therapy effectively combats minimal residual leukemia in immunodeficient mice.

Adoptive transfer of donor-derived cytolytic T-lymphocytes (CTL) has evolved as a promising strategy to improve graft-versus-leukemia (GvL) effects in allogeneic hematopoietic stem-cell transplantation. However, durable clinical responses are often hampered by limited capability of transferred T cells to establish effective and sustained antitumor immunity in vivo. We therefore analyzed GvL responses of acute myeloid leukemia (AML)-reactive CD8(+) CTL with central and effector memory phenotype in a new allogeneic donor-patient specific humanized mouse model. CTL lines and clones obtained upon stimulation of naive CD45RA(+) donor CD8(+) T cells with either single HLA antigen-mismatched or HLA-matched primary AML blasts, respectively, elicited strong leukemia reactivity during cytokine-optimized short to intermediate (i.e., 2-8 weeks) culture periods. Single doses of CTL were intravenously infused into NOD/scidIL2Rcg(null) mice when engraftment with patient AML reached bone marrow infiltration of 1-5%, clinically defining minimal residual disease status. This treatment resulted in complete regression of HLA-mismatched and strong reduction of HLA-matched AML infiltration, respectively. Most importantly, mice receiving AML-reactive CTL showed significantly prolonged survival. Transferred CTL were detectable in murine bone marrow and spleen and demonstrated sustained AML-reactivity ex vivo. Moreover, injections with human IL-15 clearly promoted CTL persistence. In summary, we show that naive donor-derived CD8(+) CTL effectively combat patient AML blasts in immunodeficient mice. The donor-patient specific humanized mouse model appears suitable to evaluate therapeutic efficacy of AML-reactive CTL before adoptive transfer into patients. It may further help to identify powerful leukemia rejection antigens and T-cell receptors for redirecting immunity to leukemias even in a patient-individualized manner.

A Model of Spirituality for Ageing Muslims.

Spirituality's influence on general well-being and its association with healthy ageing has been studied extensively. However, a different perspective has to be brought in when dealing with spirituality issues of ageing Muslims. Central to this perspective is the intertwining of religion and spirituality in Islam. This article will contribute to the understanding of the nature of Islamic spirituality and its immense importance in the life of a practicing ageing Muslim. Consequently, it will help care providers to include appropriate spiritual care in the care repertoire of a Muslim care recipient. It is assumed that the framework for a model of spirituality based on Islamic religious beliefs would help contextualise the relationship between spirituality and ageing Muslims. Not only challenges, but also the opportunities that old age provides for charting the spiritual journey have underpinned this model.

The Sensitivity of Magnetic Resonance Imaging and Ultrasonography in Detecting Rotator Cuff Tears.

Shoulder pain is a common cause of morbidity in the general population. Differential diagnosis may be difficult. Soft tissue shoulder disorders are the most common causes of shoulder pain. Noninvasive imaging techniques can reveal rotator cuff (RC) pathologies. These include ultrasonography (US) and MRI. Minimally invasive techniques such as magnetic resonance arthrography (MRA) can also be recruited when required. We conducted a retrospective study of 61 consecutive patients with shoulder pain, who had undergone preoperative imaging in the form of US or MRI and subsequently proceeded to arthroscopic surgery. Nineteen patients had a US and 42 had an MRI preoperative imaging evaluation. This evaluation was compared to the operative findings. The US sensitivity was 87%, while specificity was 63%. The MRI accuracy rose to a sensitivity of 95% when specificity was 72%. The positive predictive value (PPV) was 64% for US and 76% for MRI. The negative predictive value (NPV) was 87% for US and 94% for MRI. The overall accuracy of the ultrasound was 73% and of the MRI 83%.

Depletion of alloreactive donor T lymphocytes by CD95-mediated activation-induced cell death retains antileukemic, antiviral, and immunoregulatory T cell immunity.

In allogeneic hematopoietic stem cell transplantation (AHSCT) graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect are closely but not invariably linked. Thus, harnessing donor lymphocyte mediated GVL immunity and separating it from GVHD is of particular interest. Based on results obtained in murine models we have explored the CD95-mediated activation-induced cell death (AICD) strategy to selectively deplete alloreactivity in human donor T lymphocytes in vitro. Following stimulation of CD3(+) T cells isolated from HLA-A* 0201-positive donors with HLA or minor histocompatibility antigen mismatched hematopoietic or nonhematopoietic cells in the presence of agonistic anti-CD95 antibody, we achieved efficient and selective allodepletion across major and minor histocompatibility mismatched barriers. Residual alloreactivity was in the range of 10% and 25% using hematopoietic cells and primary keratinocytes as alloantigen-presenting cells, respectively. CD8(+) T cells specific for HLA-A * 0201-associated cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Wilms tumor 1 peptide epitopes were retained at significant numbers within the allodepleted donor lymphocyte subsets. Additionally, CD4(+) FoxP3(+) regulatory T cells persisted after the allodepletion procedure. Our results show that AICD induced by an agonistic anti-CD95 antibody might be useful to generate allodepleted donor lymphocyte products with preserved beneficial immune functions for patients undergoing AHSCT.

Failure of a Medial Unicompartmental Knee Replacement due to Metal Allergy.

Metal hypersensitivity is an uncommon complication of knee arthroplasty that can lead to significant functional impairment and aseptic prosthesis failure. We describe the case of a 65-yr-old female patient who presented with persistent pain, swelling, and instability 1 yr after medial unicompartmental knee arthroplasty (UKA). The patient had no history of trauma or fall. The initial clinical examination showed good range of movement in the knee joint and no signs of infection or inflammation. Initial radiographs did not reveal aseptic loosening of the implant. Inflammatory markers were normal and the patient was sent for a bone scintigraphy that revealed increased uptake of the femoral implant. Pain deteriorated during the proceeding weeks, and repeated radiographs revealed loosening and dislocation of the femoral implant. We performed a nickel lymphocyte proliferation skin allergy test that resulted in a positive reaction. Revision total knee arthroplasty was performed using an oxynium (zirconium metal alloy) implant with intraoperative tissue pathology and postoperative leukocyte transformation testing that confirmed metal hypersensitivity as the cause for aseptic implant failure. This case report demonstrates that clinical and laboratory signs suggesting metal hypersensitivity in knee arthroplasty can suggest early loosening and failure of the implant.

Condylar Joint Fusion and Stabilization (by Screws and Plates) in Nontraumatic Atlanto-Occipital Dislocation: Technical Report of 2 Cases.

BACKGROUND: Nontraumatic spontaneous atlanto-occipital dislocation (AOD) is rare. In this report, we discuss the technical steps of condylar joint fusion and stabilization (by screws and plates) in nontraumatic AOD. To the best of our knowledge, it is the first report of such techniques. MATERIAL AND METHODS: A young girl and a young man with progressive quadriparesis due to nontraumatic spontaneous atlanto-occipital dislocation were managed by microsurgical reduction, fusion, and stabilization of the joint by occipital condylar and C1 lateral mass screw and plate fixation after mobilization of vertebral artery. RESULT: In both cases, condylar joints fixation and fusion were done successfully. CONCLUSION: Condylar joint stabilization and fusion may be a good or alternative option for AOD.

Munchausen's syndrome presenting as rectal foreign body insertion: a case report.

BACKGROUND: This case report shows that Munchausen's syndrome can present as rectal foreign body insertion. Although the presentation of rectal foreign bodies has frequently been described in the medical literature, the insertion of foreign bodies into the rectum for reasons other than sexual gratification has rarely been considered. CASE PRESENTATION: A 30 year old, unmarried Caucasian male presented with a history of having been sexually assaulted five days earlier in a nearby city by a group of unknown males. He reported that during the assault a glass bottle was forcibly inserted into his rectum and the bottle neck broke. On examination, there was no evidence of external injury to the patient. Further assessment lead to a diagnosis of Munchausen's syndrome. The rationale for this is explained. A description and summary of current knowledge about the condition is also provided, including appropriate treatment approaches. CONCLUSION: This case report is important because assumptions regarding the motivation for insertion of foreign bodies into the rectum may lead to the diagnosis of Munchausen's syndrome being missed. This would result in the appropriate course of action, with regard to treatment, not being followed. It is suggested that clinicians consider the specific motivation for the behaviour in all cases of rectal foreign body insertion, including the possibility of factitious disorder such as Munchausen's syndrome, and avoid any assumption that it has been carried out for the purpose of sexual gratification. Early involvement of psychiatrists is recommended. Cases of Munchausen's syndrome presenting as rectal foreign body insertion may be identified and addressed more effectively using the approach described.

Selective depletion of alloreactive T lymphocytes using patient-derived nonhematopoietic stimulator cells in allograft engineering.

BACKGROUND: Selective depletion of alloreactive T cells in vitro results in efficient graft-versus-host disease prophylaxis in allogeneic hematopoietic stem-cell transplantation, but it is accompanied by increased recurrence of leukemia. To spare donor T-cell-mediated graft-versus-leukemia immunity against hematopoiesis-restricted minor histocompatibility (minor-H) antigens, we explored the use of patient-derived nonhematopoietic antigen-presenting cells (APC) as allogeneic stimulators for selective allodepletion in leukemia-reactive donor T-cell lines. METHODS: Primary keratinocytes, dermal fibroblasts, and bone marrow fibroblasts were generated from skin biopsies and diagnostic bone marrow aspirates of acute myeloid leukemia patients in vitro. Cell cultures were analyzed for expansion, phenotype, and immunostimulatory capacity in comparison with CD40-activated B cells as professional APC. In addition, nonhematopoietic APCs were used for selective allodepletion in vitro. RESULTS: Patient-derived fibroblasts could be reliably expanded to large cell numbers, whereas keratinocytes had limited growth potential. Interferon-gamma-pretreated fibroblasts showed increased expression of human leukocyte antigen (HLA)-class I and II molecules, CD40, and CD54. Fibroblasts and CD40-activated B cells comparably stimulated HLA-A*0301-specific CD8 T cells after transient expression of HLA-A*0301 as a model alloantigen. Finally, fibroblasts could be effectively applied to selectively deplete alloreactivity within leukemia-reactive donor CD8 T-cell lines by targeting the activation-induced antigen CD137. CONCLUSIONS: Primary fibroblasts can be efficiently used as allogeneic nonhematopoietic APC for selective depletion of donor T cells reactive to HLA and ubiquitously expressed minor-H antigen disparities in leukemia-stimulated CD8 T-cell lines. Therefore, harnessing alloreactivity to hematopoietic minor-H antigens in addition to leukemia-associated antigens might increase graft-versus-leukemia immunity of donor lymphocyte grafts in allogeneic hematopoietic stem-cell transplantation.

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines.

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.