Successful transplantation of allogeneic organs is an important objective in modern medicine. However, sophisticated immune defense mechanisms, primarily evolved to combat infections, often work against medical transplantation. To investigate the roles of natural and adaptive immune responses in transplant rejection, we functionally inactivated key effector systems of the innate (NK cells) and the adaptive immune system (CD28-mediated costimulation of T cells) in mice. Neither of these interventions alone led to acceptance of allogeneic vascularized cardiac grafts. In contrast, inhibition of NK-receptor-bearing cells combined with CD28-costimulation blockade established long-term graft acceptance. These results indicate a concerted interplay between innate and adaptive immune surveillance for graft rejection. Thus we suggest that inactivation of NK-receptor-bearing cells could be a new strategy for successful survival of solid-organ transplants.

Dendritic cells (DCs)* fulfill an important regulatory function at the interface of the innate and adaptive immune system. The thymus and activation-regulated chemokine (TARC/CCL17) is produced by DCs and facilitates the attraction of activated T cells. Using a fluorescence-based in vivo reporter system, we show that CCL17 expression in mice is found in activated Langerhans cells and mature DCs located in various lymphoid and nonlymphoid organs, and is up-regulated after stimulation with Toll-like receptor ligands. DCs expressing CCL17 belong to the CD11b+CD8−Dec205+ DC subset, including the myeloid-related DCs located in the subepithelial dome of Peyer's patches. CCL17-deficient mice mount diminished T cell–dependent contact hypersensitivity responses and display a deficiency in rejection of allogeneic organ transplants. In contrast to lymphoid organs located at external barriers of the skin and mucosa, CCL17 is not expressed in the spleen, even after systemic microbial challenge or after in vitro stimulation. These findings indicate that CCL17 production is a hallmark of local DC stimulation in peripheral organs but is absent from the spleen as a filter of blood-borne antigens.

SUMMARYGenetically determined responsiveness to microbial stimuli such as lipopolysaccharide (LPS) may affect the pathophysiology of human sepsis. The D299G mutation in human Toll-like receptor-4 (TLR4) impairs LPS signalling in homozygous and heterozygous individuals. To investigate whether the presence of the TLR4(D299G) mutation may correlate with the development or outcome of sepsis following major visceral surgery the presence of TLR4(D299G) mutation was analysed in 307 Caucasian patients (154 without and 153 with sepsis). Sepsis was caused in 84% of patients by polymicrobial infection. The presence of the mutant TLR4 did not signi®cantly correlate with development or outcome of sepsis. Serum levels of tumour necrosis factor, interleukin (IL)-10, and IL-6 at sepsis onset did not signi®cantly differ between patients carrying wild-type and mutant TLR4. Moreover, studies in a murine model of polymicrobial septic peritonitis demonstrated that TLR4-de®ciency did neither in¯uence the systemic cytokine response nor the development of organ injury. The results suggest that the signalling capacity of TLR4 as affected by loss-offunction mutations does not in¯uence human or experimental sepsis caused by polymicrobial infection. Thus, in polymicrobial infection, other innate immune receptors may compensate for TLR4 defects.

Intra-abdominal infection in patients following major visceral surgery is associated with high mortality. Using a macrophage depletion technique, we demonstrate that in murine septic peritonitis, Kupffer cells are a major source of systemic IL-10 levels. Kupffer cell-depleted mice were highly susceptible to the lethal effects of septic peritonitis and exhibited an increased bacterial load. Kupffer cell-depleted mice were protected by the administration of an IL-10-Fc fusion protein. Loss of Kupffer cell-derived IL-10 was associated with a weak increase in serum IL-12 levels, whereas TNF, IL-1α, and IL-18 levels were not significantly elevated, suggesting that the loss of Kupffer cell-derived IL-10 did not result in a toxic cytokine release syndrome. Instead, loss of Kupffer cell-derived IL-10 was associated with a reduced splenocyte production of IFN-γ that is required for immune protection in murine septic peritonitis. Therefore, the results suggest that the protective function of IL-10 in septic peritonitis may not be restricted to the anti-inflammatory activities of IL-10.

No abstract

Chronic graft rejection mediated by cellular immune responses still poses a serious clinical problem in transplant surgery. Chemokines coordinate the recruitment of leukocytes in inflammatory and immune responses. Their precise functions in the rejection of allografts are still ill defined. This study investigates the role of chemokine receptor 4 (CCR4) in acute and chronic cardiac allograft rejection in mice. Allogeneic hearts were transplanted into CCR4 deficient (CCR4 -/-) and control recipients. Reverse transcription-PCR showed transcription of macrophage-derived chemokine and thymus and activation-regulated chemokine, the cognate chemokine ligands of CCR4, within the graft. Compared to wild-type controls, acute allograft rejection in CCR4 -/-recipients was only slightly prolonged. In contrast, in a gallium nitrate chronic cardiac allograft rejection model, cardiac graft survival was significantly prolonged in CCR4 -/-recipients. A relative increase in the percentage of graft infiltrating CD8 + T cells in CCR4 -/-recipients was observed 30 days after transplantation and was accompanied by a decrease in CD4 + T cells. Moreover, the percentage of NK1.1 + CD3 + graft-infiltrating cells was significantly reduced on day 5 and day 30 post transplantation. These findings indicate that CCR4 is involved in the recruitment of NK1.1 + CD3 + cells into cardiac allografts and clearly establish an important and novel role for CCR4 in chronic graft rejection.

No abstract

Summary With the more frequent use of organs from elderly donors, the risk of transmitting tumor cells to the recipient increases. We report a case in which anaplastic carcinoma tumor cells from an organ‐donor were transmitted to a kidney transplantation recipient. The donor's metastatic disease was discovered 7 days after harvest of the kidney following a brain biopsy undertaken at admission of the donor. The risk of transmitting the disease was generally estimated as so small that the excellently functioning kidney was not removed. Twelve weeks later, however, malignant cells were found in a biopsy of the transplanted kidney. The organ was removed immediately, but the intraoperative situs showed advanced disease with lymph‐node‐metastasis. Twelve months later no tumor progress could be detected. This case shows that there is considerable risk of transmitting formerly undetected cancer in elderly donors. Autopsies of donors who are older than 60 years of age should be routinely performed after organ donation.