Biomedical subjects

Andrew D Luster

Publications and source records attributed to Andrew D Luster.

75 records · Page 5Linked to original sources

PubMed2002

The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection.

Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4(+) T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5(-/-) (C57BL/6) recipients survived significantly longer (mean survival time, 38 +/- 8 days) compared with those transplanted into wild-type control mice (10 +/- 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5(-/-) animals without other treatment survived >90 days. In CCR5(-/-) mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-gamma was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzyme-linked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection.

Animals↗

PubMedDate not supplied

Chemokines in islet allograft rejection.

Chemokines have emerged as important regulators in the development, differentiation, and anatomic distribution of leukocytes. Studies of renal and cardiac allograft biopsies have revealed that the expression of many chemokine receptors and their ligands was associated with acute allograft rejection. However, the importance of these chemokine receptor systems varies in the host response to a particular allograft. In this regard, CXCR3 appears to play a more important role in cardiac allograft rejection than CCR2 and CCR5. We have found that CCR2, CCR5, and CXCR3 and their ligands, as well as Th1 cytokines are induced to high levels in rejecting islet allografts. Interestingly, targeting CCR5 resulted in a significant prolongation of islet allograft survival. This prolongation was associated with a Th2 response. Our data indicate that in the process of acute rejection, the temporal expression and the ultimate function of a given chemokine vary among different organs or tissues. Hence, each organ or tissue may require a unique set of chemokines to generate acute rejection. Targeting the appropriate chemokine receptors may provide a clinically useful strategy to prevent islet allograft rejection.

Acute Disease↗

PubMedDate not supplied

BLT1 and BLT2: the leukotriene B(4) receptors.

Two receptors for leukotriene B(4) (LTB(4)) have been molecularly identified: BLT1 and BLT2. Both receptors are G protein-coupled seven transmembrane domain receptors, whose genes are located in very close proximity to each other in the human and mouse genomes. The two receptors differ in their affinity and specificity for LTB(4): BLT1 is a high-affinity receptor specific for LTB(4), whereas BLT2 is a low-affinity receptor that also binds other eicosanoids. The two receptors also differ in their pattern of expression with BLT1 being expressed primarily in leukocytes, whereas BLT2 is expressed more ubiquitously. By mediating the activities of LTB(4), these receptors participate both in host immune responses and in the pathogenesis of inflammatory diseases. Reduced disease severity in animal inflammatory models seen with LTB(4) receptor antagonists and in mice with targeted deletion of BLT1 have revealed important roles for LTB(4) and its receptors in regulating pathologic inflammation.

Amino Acid Sequence↗