Role of 4-1BB in Allograft Rejection Mediated by CD8+ T Cells

Blockade of traditional costimulatory molecules fails to inhibit rejection in many models where CD8+ T cells are sufficient to mediate rejection. This observation demonstrates that in many settings CD8+ T cells are not dependent upon CD28 or CD154 signals to mediate rejection. 4-1BB (CD137) has been shown to be an important regulatory molecule for CD8+ T cells in a variety of nontransplant models. Here we show that blocking the 4-1BB pathway significantly inhibited rejection of intestinal allografts by CD8+ but not CD4+ T cells. This effect was associated with significantly decreased expression of the genes encoding TNFalpha and secondary lymphoid chemokine (SLC) within the spleens of recipient mice. Disruption of the 4-1BB pathway also impaired the priming of alloantigen-specific CD8+ T cells and the accumulation of recipient dendritic cells within the spleen. These data directly demonstrate an important role for 4-1BB in allograft rejection; particularly rejection mediated by CD8+ T cells. Our data suggest that in addition to providing a direct costimulatory signal to T cells, the 4-1BB pathway may regulate other important steps in the immune response such as the migration of T cells and dendritic cells.     

The beta subunit of human chorionic gonadotropin lacks specificity for malignant cells in serous effusions.

The cytologic diagnosis of malignancy is frequently straightforward. For difficult cases, multiple immunostains and immunostain panels have been investigated without consensus. beta-human chorionic gonadotropin (hCG) has been reportedly expressed in malignancies, but not in normal tissue. HCG also has been reported as a specific marker of metastases in serous fluids when detected with laboratory assays. We investigated the clinical utility of hCG in this cytologic setting. A total of 97 cases of benign and malignant effusions were studied. Each case was immunostained with monoclonal hCG using the avidin-biotin technique and diaminobenzidine as a chromogen. Additionally, a mucicarmine stain was performed on most cases. Cases were evaluated for hCG expression and mucin in a blinded fashion. After the cases were reviewed, the diagnoses were unblinded and staining patterns were evaluated. Of the 47 benign cases studied, 23 (49%) exhibited immunoreactivity to hCG in at least 5% of mesothelial cells present. In contrast, 28 of 44 (64%) adenocarcionomas exhibited a similar degree of immunostaining. In all, 21 (48%) of the adenocarcinomas were also positive for mucin; five of these mucin-positive cases were negative for hCG. The combination of mucin and hCG detected 33 of 44 (75%) adenocarcinomas. We conclude that hCG lacks the specificity for malignant cells to be of clinical use in effusion cytology.     

Combined Excimer Laser and Topical Tacrolimus for the Treatment of Vitiligo: A Pilot Study

Background. Vitiligo is an acquired skin disorder that is characterized by well-defined, often symmetric white patches. Although current therapeutic modalities are directed toward increasing melanocyte melanin production, few treatment modalities address the immunologic nature of the disease.
Objective. To determine whether excimer laser, a known therapeutic modality, in combination with tacrolimus, a topical immunomodulator, accelerate response time and/or improve the degree of response in patients with this disorder.
Methods. Eight subjects diagnosed with vitiligo were recruited to participate in this institutional review board–approved double-blind, placebo-controlled study. Twenty-four symmetric vitiliginous patches (elbows, knees) from eight subjects received excimer laser treatment three times per week for 24 treatments or 10 weeks. Additionally, topical tacrolimus 0.1% ointment (Protopic) and placebo (Aquaphor) were applied to randomized patches (left or right) twice daily throughout the length of the trial. Vitiliginous patches were monitored with photographs at baseline, every 2 weeks, and 6 months after treatment. Biopsies were performed on subjects with significant results.
Results. Twenty vitiliginous patches from six subjects qualified for evaluation. Fifty percent of patches treated with combination excimer laser and tacrolimus achieved a successful response (75% repigmentation) compared with 20% for the placebo group. Subjects who responded successfully repigmented faster (19%) with combination therapy compared with excimer laser alone. Additionally, three subjects experienced transient hyperpigmentation in lesions treated with combination therapy.
Conclusion. Combining topical immunomodulators with known phototherapeutic modalities may represent a key advancement in the treatment of disease.     

Anterior Communicating Artery Aneurysm Following Radiation Therapy for Optic Glioma: Report of a Case and Review of the Literature

A 42-year-old female presented with subarachnoid hemorrhage (SAH), presumably from a radiation-induced anterior communicating artery aneurysm. Six years earlier, she had undergone radiation treatment for an optic glioma that was diagnosed based on imaging criteria. The aneurysm was successfully clipped, and the optic glioma was biopsied to verify the diagnosis histologically. Radiation-induced cerebral aneurysms often manifest with a fatal SAH. These aneurysms typically develop in the field of radiation and are diagnosed a mean of 8.52 years after radiation. Rarely, the aneurysm sac thromboses spontaneously. Clipping or coiling of the aneurysm can be an effective treatment.     

Computer simulation training enhances patient comfort during endoscopy.

BACKGROUND & AIMS: Computer-based endoscopy simulator (CBES) training's impact on patient-based outcomes has never been examined. This study examines whether the endoscopy skills of trainees are improved and patient discomfort is reduced as a result of CBES training. METHODS: From July 2001-June 2002, 38 residents received either 1 week of patient-based training (PBT) alone in flexible sigmoidoscopy (FS) or 3 hours of simulator-based training (SBT) before a week of training in FS. Patients completed questionnaires grading the discomfort experienced during endoscopy (1, no pain; 10, worst pain of life). In addition, residents' performance was graded by the supervising staff and themselves with 8 performance parameters by using a 1-10 Likert scale (1, strongly agree; 5, neutral; 10, strongly disagree). RESULTS: Nineteen SBT and 19 PBT residents performed 150 and 175 FS, respectively. During this same period, staff completed 585 FS. The median patient discomfort score for SBT residents was significantly less than for PBT residents, 3 (25%-75% interquartile range [IQR], 2-5) vs. 4 (IQR, 2-6) (P < 0.01). Discomfort scores for both resident groups were significantly greater than those recorded by staff endoscopists, 2 (IQR, 1-4) (P < 0.01). No difference was seen in the residents' procedural skill scores. Resident self-evaluation scores were significantly greater than those received from the supervising staff. CONCLUSIONS: Increased patient comfort resulted from simulation training, demonstrating that CBES training has a direct benefit to the patient. Although no measurable impact on residents' performance skills was observed, we do demonstrate that residents perceive themselves as having acquired greater endoscopic skills in contrast to staff evaluations.