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Introduction: An effective salvage regimen for the reinduction of remission is lacking for refractory or relapsed primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of cytarabine plus temozolomide in treating r/r PCNSL and to explore the associated prognostic factors., Methods: A single-center retrospective cohort study was conducted to assess the efficacy and safety of cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping was performed on peripheral blood samples., Results: Thirty PCNSL patients receiving an AT regimen (cytarabine 3 g/m 2 for 2 days combined with temozolomide 150 mg/m 2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25-79 years). A total of 43.4% of patients (13/30) achieved an overall response within a median follow-up of 16 months (95% confidence interval [CI]: 11-23 months). The median PFS and OS of the cohort were 1.5 months (95% CI: 1-4 months) and 19.5 months (95% CI: 11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate ( p  = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) ( p  = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with PFS ( p  = 0.043). However, KIR/HLA-B genotypes had no impact on the OS of the cohort. The toxicity of AT treatment was mild and manageable., Conclusion: The AT regimen was well tolerated, and patients with specific KIR-HLA genotypes may benefit from this regimen.

Pediatric recipients of living-donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi-allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post-Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr-tol), but not in 50 intolerant patients (Gr-intol). The Gr-intol consisted of 24 patients with rejection (Gr-rej) and 26 with fibrosis of grafts (Gr-fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11-7.02, P = 0.03], was a positive independent predictor, whereas HLA-A mismatch (0.18, 0.03-0.91, P = 0.04) was a negative predictor. HLA-DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr-intol (4.9%) compared with Gr-tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr-Tol (P = 0.02). Although HLA-B mismatch (8.73, 1.09-70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA-A match and the later predominance of Tregs are factors associated with OT., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

Background: A synthetic peptide corresponding to residues 75-84 of the alpha1 domain of HLA-B7 molecule (HLA-B7.75-84 [Allotrap]) inhibits cytotoxic T cell function in vitro and, when combined with subtherapeutic doses of cyclosporine (CsA), prolongs allogeneic cardiac survival. We now report the effects of HLA-B7.75-84 in the Lewis --> Fischer 344 rat model of chronic cardiac allograft rejection., Methods: Animals were treated with CsA (5 mg/kg/day s.c.) alone or with CsA plus alternate-day HLA-B7.75-84 (20 mg/kg/day i.p.) for 30 days. Allografts harvested at day 100 were evaluated by histology and immunohistology., Results: HLA-B7.75-84 plus CsA prolonged allograft survival (75% of allografts survived >90 days) compared with CsA alone (27% of allografts survived >90 days) (P<0.05). Histologic examination of control allografts showed dense cellular infiltrates and moderate transplant arteriosclerosis (>75% of arteries showed 10-20% occlusion). Infiltrating leukocytes consisted of macrophages (>75% cells), T cells (10-20%), and rare natural killer cells (<5%). Cell activation was shown by expression of major histocompatibility complex class II antigens (>75%), interleukin (IL) 2 receptor (5-10%), and staining for IL-2 (approximately 5% of intragraft mononuclear cells), interferon-gamma (5-10%) and tumor necrosis factor-alpha (approximately 20%). Leukocytes and vessels also showed labeling for the fibrogenic cytokine, transforming growth factor-beta, and all vessels showed dense deposition of IgG (IgG2a, IgG2b) and C3. The addition of HLA-B7.75-84 decreased overall cellularity (P<0.01) without affecting the composition of the infiltrate, but completely prevented transplant arteriosclerosis, diminished myocardial injury, and abrogated expression of IL-2R, IL-2, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. HLA-B7.75-84 also blunted the humoral response, which resulted in a predominance of vascular deposition of the non-complement-fixing IgG2c isotype and a concomitant decrease in C3., Conclusions: Therapy with synthetic class I major histocompatibility complex peptide (HLA-B7.75-84) attenuates key histologic features of graft arteriosclerosis, in association with inhibition of multiple cytokines and growth factors and modulation of host alloantibody responses in vivo, which is of interest since Allotrap is currently undergoing clinical trials.

Background: The ultimate treatment for severe short bowel syndrome is small bowel transplantation (SBT). Current immunosuppression for SBT is relatively ineffective and toxic. Peptides derived from residues 75-84 of the HLA-B7 molecule are immunomodulatory in vitro, and in rodents, when combined with subtherapeutic doses of cyclosporine (CsA), prolong cardiac and skin allograft survival without altering the recipient's rejection kinetics to third party allografts. We investigated the effects of HLA-B7 peptide fragment in a rat model of SBT., Methods: Heterotopic allogeneic SBT was performed in Dagouti (RT1a) to Lewis (RT1l) high-responder rat strain combination. B7.75-84 (40 mg/kg/d) and subtherapeutic CsA (10 mg/kg/d) were administered alone, or in combination, by gavage to allograft recipients on days 0 to 4 after SBT. Recipient pretreatment with B7.75-84 on days -14, -12, -10, and -7 followed by subtherapeutic CsA on days 0 to 4 after SBT was also carried out. Graft rejection was determined by the presence of a palpable abdominal mass on daily examination or by loss of more than 10% initial body weight., Results: Without immunosuppression allografts rejected at a median time of 6 days (range, 5 to 7; n = 7). This was not significantly altered with either CsA therapy alone (median 6 days; range, 6 to 7; n = 6) or B7.75-84 alone (median, 5 days; range, 5 to 6; n = 6). Recipient combination therapy with B7.75-84 and CsA after allografting significantly prolonged allograft survival (median, 11 days; range, 9 to 13; n = 9), as did recipient B7.75-84 pretransplant therapy (median, 10 days; range, 9 to 12; n = 6), when administered over a 2-week period before allografting., Conclusion: Post-SBT recipient treatment with B7.75-84 produced statistically significant improvement in allograft survival only after combination with subtherapeutic CsA. Recipient pre-SBT treatment with B7.75-84 alone however, resulted in statistically significant improvement in allograft survival in combination with post-SBT subtherapeutic CsA. These synergistic effects may be valuable in achieving improved SBT survival clinically and warrant further exploration.