A. Shefizadeh

Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection.

Chemokine-chemokine receptor interactions orchestrate mononuclear cells recruitment to the allograft, leading to acute and chronic rejection. Despite biologic redundancy, several experimental studies have demonstrated the importance of CXCR3 and CCR5 in acute rejection of allografts. In these studies, deficiency or blockade of CXCR3 or CCR5 led to prolongation of allograft survival, yet allografts were ultimately lost to acute rejection. Given the above findings and the specificity of mononuclear cells bearing CXCR3 and CCR5, we hypothesized that combined blockade of CXCR3 and CCR5 will lead to indefinite (>100 days) graft survival in a full MHC-mismatched murine cardiac allograft model. The donor hearts in the control group were rejected in 6 ± 1 days after transplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival >15-fold vs the control group; all allografts survived for >100 days. More importantly, the donor hearts did not display any intimal lesions characteristic of chronic rejection. Further analysis of the donor hearts in the CXCR3/CCR5 blockade group demonstrated graft infiltration with CD4+CD25+ T cells expressing the Foxp3 gene. Depletion of CD25+ cells in the combined CXCR3 and CCR5 blockade group resulted in acute rejection of the allografts in 22 ± 2 days. Combined CXCR3 and CCR5 blockade also reduced alloantigen-specific T lymphocyte proliferation. Combined CXCR3 and CCR5 blockade is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated, in part, by CD25+ regulatory T cell recruitment and control of T lymphocyte proliferation.

Inflammation/oxidation in chronic rejection: apolipoprotein a-i mimetic peptide reduces chronic rejection of transplanted hearts.

Background. Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. Strategies to control CAV traditionally have focused on lymphocyte functions. We hypothesized that D-4F, an apoA-I mimetic peptide with potent anti-inflammatory/antioxidant properties, will attenuate CAV. Methods. We used a previously characterized murine model of CAV. B6.C-H2bm12 hearts were heterotopically transplanted into C57BL/6 mice. Recipient mice were treated with either 20 &mgr;g of D-4F or carrier daily. Donor hearts were harvested on day 24 after transplantation. Results. Treatment of recipients with D-4F reduced the severity of intimal lesions (62.5±3.4% vs. 31.1±8.7%, P<0.009). Treatment also resulted in a decrease in the number of graft-infiltrating CD4 and CD8 lymphocytes and CXCR3+ T-lymphocyte subsets. Heme oxygenase-1 (HO-1) gene transcript in the donor hearts was up-regulated with D-4F treatment, and HO-1 blockade partially reversed the beneficial effects of D-4F. In vitro studies showed that D-4F reduced allogeneic T-lymphocyte proliferation and effector cytokine production. These processes were HO-1 independent. Conclusion. This study suggests that D-4F, a prototypical apoA-I mimetic peptide, is effective in controlling CAV via induction of HO-1 in the graft and a direct effect on T-lymphocyte function. This class of peptides with anti-inflammatory/antioxidant properties provides a novel strategy in the treatment of CAV.

Liberalization of donor criteria for lung transplantation

Purpose of reviewThe greatest factor limiting the number of lung transplants performed each year is the availability of acceptable donors. Liberalization of currently accepted donor criteria would allow for an increase in the number of donor lungs procurable. This would help treat those patients on the ever-expanding transplant waiting list. Recent findingsThe generally accepted criteria for an acceptable donor are: age less than 55 years, clear chest radiograph, PaO2/FiO2 ratio greater than 300, and a clear bronchoscopy. Historically these parameters have little evidence-based support. Numerous recent studies of patients transplanted with nonstandard lungs show no difference in outcomes when compared with those transplanted with lungs that met all criteria. However, a few studies have noted that certain donor criteria could predict short-term adverse outcome. The specific criteria implicated as risk factors are donor age and prolonged graft ischemic time in conjunction with advanced donor age. Studies assessing outcomes beyond the first posttransplant year have found no difference between recipients of standard and nonstandard donor lungs. SummaryIncreased waiting time and recent advances in transplant procurement, preservation, and operative technique warrant the expansion of current standard donor criteria. Most contemporary evidence demonstrates no difference in outcome when nonstandard donors are used. Although caution is justified when transplanting nonstandard lungs with multiple risk factors into high-risk patients, liberalization of the criteria now is well supported.