Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy.

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.

Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells.

The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T-cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study the mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8(+) T-cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T-cell trafficking to the graft but not memory T-cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.

Diagnostic challenges in the evaluation of hepatic grafts from donors with HELLP syndrome: case report and review of the literature.

HELLP syndrome (hemolysis, elevated liver function tests, low platelets) is a rare complication of pregnancy that can result in severe complications such as hepatic infarction, subcapsular liver hematomas, and maternal brain death from cerebral hemorrhage. Recently, several investigators have described cases of successful transplantation using livers procured from donors who suffered brain death as a result of HELLP syndrome. However, this new class of marginal liver donors must be approached with caution. We report the case of a 28-year-old pregnant woman who suffered brain death due to HELLP syndrome and was subsequently evaluated for potential liver donation. Although her transaminitis and other liver function tests were markedly improving during the final days of her hospital course, her liver demonstrated segments of necrosis during attempted procurement, and the histology revealed extensive centrilobular necrosis. This case suggests that peak values of serum transaminases, as well as partial resolution of transaminitis, appear to have limited predictive ability in determining the suitability of the hepatic graft for transplantation. Thus, donors with HELLP syndrome should be approached with caution, even in the setting of laboratory values suggesting minimal or resolving hepatic injury. Furthermore, there should be an additional emphasis on obtaining and reviewing histology of the potential graft to determine its suitability for transplantation.

Macrophage depletion suppresses cardiac allograft vasculopathy in mice.

Cardiac allograft vasculopathy (CAV) is a major source of late posttransplant mortality. Although numerous cell types are implicated in the pathogenesis of CAV, it is unclear which cells actually induce the vascular damage that results in intimal proliferation. Because macrophages are abundant in CAV lesions and are capable of producing growth factors implicated in neointimal proliferation, they are leading end-effector candidates. Macrophages were depleted in a murine heterotopic cardiac transplant system known to develop fulminant CAV lesions. C57BL/6 hearts were transplanted into (C57BL/6 x BALB/c)F(1) recipients, which then received anti-macrophage therapy with intraperitoneal carrageenan or i.v. gadolinium. Intraperitoneal carrageenan treatment depleted macrophages by 30-80% with minimal effects upon T, B or NK cells as confirmed by flow cytometry and NK cytotoxicity assays. Carrageenan treatment led to a 70% reduction in the development of CAV, as compared to mock-treated controls (p = 0.01), which correlated with the degree of macrophage depletion. Inhibition of macrophage phagocytosis alone with gadolinium failed to prevent CAV. Macrophages may represent the end-effector cells in a final common pathway towards CAV independent of T-cell or B-cell alloreactivity and exert their injurious effects through mechanisms related to cytokine/growth factor production rather than phagocytosis.

Using DNA chips to unravel the genetics of type 1 diabetes.

Thousands of genes are currently being discovered by sequencing the human genome. Of these, hundreds if not thousands fall into regions of the genome identified by genetic studies as linked to the development of type 1 diabetes. Inheritance patterns for these regions suggest that diabetes results from the combinatorial interaction of susceptibility loci. The study of such complex events will require technologies that can simultaneously evaluate expression profiles and allelic differences for all these genes in order to dissect the mechanisms responsible for the development of disease. We will argue that DNA microarrays are the natural vehicle for the exploration of diabetes-related gene clusters, and the application of these arrays to understanding diabetes is discussed.