An Essential Contribution by IFN-γ to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts

Diamond, Andrew S.; Gill, Ronald G.

doi:10.4049/jimmunol.165.1.247

Cited by 84 publications

(81 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, a major limitation in the study of the in vivo T-cell response to an allograft has been the lack of a suitable alloreactive CD4 + TCR-tg model system. Consequently, in vivo studies have been limited to using MHC class I-alloreactive TCR-tg systems in which the alloimmune response is mediated by CD8 + T cells (5)(6)(7)(8), or to using antigen-specific rather than allospecific CD4 + TCR-tg animals as surrogates (9). Recently, a novel TCR-tg MHC class II-alloreactive transplantation model has been described (10,11).…”

Section: Introductionmentioning

confidence: 99%

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Sandner

Salama

Houser

et al. 2003

American Journal of Transplantation

View full text Add to dashboard Cite

We have developed an adoptive transfer model system to visualize the dynamics of alloantigen-specific CD4 + T-cell activation in vivo. Using TCR-transgenic (tg) mice reactive to I-A bm12 , we studied the clonal expansion and differentiation of alloreactive T cells by tracking the fate of adoptively transferred TCR-tg CD4 + T cells in syngeneic mice transplanted with skin grafts expressing I-A bm12 . Following transplantation, alloantigen-specific TCR-tg CD4 + T-cell expansion was observed initially in the draining lymph nodes followed by the spleen. TCR-tg CD4 + T cells up-regulated CD69 and CD25 expression, developed an effector/memory surface phenotype and produced IFN-c in response to alloantigen ex vivo. Furthermore, we validate the model system as a means for studying the effects of tolerogenic regimens on alloreactive CD4 + T cells, demonstrating that CTLA4Ig inhibits alloantigen-dependent clonal expansion and effector function of TCR-tg CD4 + T cells in vivo. We describe the first model for tracking alloreactive CD4 + T-cell activation in vivo. It provides a powerful tool for studying CD4 + T-cell mediated alloimmune responses and mechanisms of tolerance induction in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

Sandner

Salama

Houser

et al. 2003

American Journal of Transplantation

View full text Add to dashboard Cite

show abstract

“…Because IFN-␥ induces CCR5 ligands, lower expression of IFN-␥ in CCR5 -/-may explain the lower expression of CCR5 ligands in this model (4). Furthermore, the ability to produce IFN-␥ has been shown to be critical for efficient CD8 ϩ T-cell-mediated rejection of islet allografts (23). Using a dextran sodium sulfate-induced colitis model, CCR5 ϩ/ϩ mice were characterized by a Th1-type response with a strong induction of IFN-␥ mRNA expression.…”

Section: Grafts From Ccr5mentioning

confidence: 99%

The Role of CC Chemokine Receptor 5 (CCR5) in Islet Allograft Rejection

et al. 2002

View full text Add to dashboard Cite

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-␥ 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 enzymelinked 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. Diabetes 51:2489 -2495, 2002 T hrough activation of the G-protein-coupled cellsurface receptor on target cells, chemokines and their receptors play a major role in the process by which leukocytes are recruited from the bloodstream into sites of inflammation, and several have been implicated in allograft rejection (1). CC chemokine receptor 5 (CCR5) is the receptor for the proinflammatory chemokines: RANTES (regulated on activation normal T-cell expressed and secreted) (CC chemokine ligand 5 [CCL5]), macrophage inflammatory protein (MIP)-1␣ (CCL3), and MIP-1␤ (CCL4) (1). Th1 cells express CCR5 and CXC chemokine receptor 3 (CXCR3) following activation, whereas activated T helper 2 (Th2) cells express CCR3, CCR4, and CCR8 (2,3). Synthesis of the chemokines MIP-1␣, MIP-1␤, and RANTES has been shown to be associated with a Th1 response (4). In vitro chemotaxis assays have shown that, whereas MIP-1␣, MIP-1␤, and RANTES were efficient chemoattractants for Th1 cells to induce a dose-dependent transmigration, Th2 cells were not attracted by these chemokines (5). In heart allografts, the early expression of some chemokines, including MIP-1␣ and MIP-1␤, subsides by day 7-9 posttransplant and is replaced by a late expression of other chemokines such as inducible protein (IP)-10 (CXCL10), monokine induced by interferon-␥ (Mig) (CXCL9) (ligands for CXCR3), and RANTES (a ligand for CCR5) (6). Met-RANTES, a CCR5 antagonist, can reduce the severity of chronic renal allograft rejection in the Lewis3 Fisher model. This effect has been attributed to blocking RANTES-induced firm adhesion of monocytes, monocyte arrest, and recruitment (7). It has recently been demonstrated that targeting CCR5 prolongs vascularized cardiac allograft survival in a mouse transplant mod...

show abstract

“…On the one hand, the presence of IFN-␥ correlates strongly with acute rejection (16), and under some conditions IFN-␥ is critical for acute rejection to proceed. For example, IFN-␥ is important for efficient islet allograft rejection mediated by primed CD8 ϩ T cells (17) and for the rejection of MHC class II disparate skin allografts (14,18,19). It is not clear whether IFN-␥ is essential in the afferent phase of the immune response (such as by enhancing graft Ag expression), in the efferent phase (such as through enhancing trafficking and infiltration of graft-reactive cells), or both.…”

mentioning

confidence: 99%

“…On the other hand, the role of IFN-␥ as a regulatory cytokine in transplantation also has become evident. IFN-␥ is not required for acute cardiac (20,21) or islet (17,22) rejection, and surprisingly can act in a protective fashion on the allograft during the early immune events following transplantation (23,24). Importantly, IFN-␥ appears to be essential for transplantation tolerance induced by costimulation blockade (22,25).…”

mentioning

confidence: 99%

Donor IFN-γ Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection

Wiseman¹,

Pietra

Kelly

et al. 2001

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Recent studies using mouse models demonstrate that CD4+ T cells are sufficient to mediate acute cardiac allograft rejection in the absence of CD8+ T cells and B cells. However, the mechanistic basis of CD4-mediated rejection is unclear. One potential mechanism of CD4-mediated rejection is via elaboration of proinflammatory cytokines such as IFN-γ. To determine whether IFN-γ is a critical cytokine in CD4-mediated acute cardiac allograft rejection, we studied whether the expression of IFN-γ receptors on the donor heart was required for CD4-mediated rejection. To investigate this possibility, purified CD4+ T cells were transferred into immune-deficient mice bearing heterotopic cardiac allografts from IFN-γ receptor-deficient (GRKO) donors. While CD4+ T cells triggered acute rejection of wild-type heart allografts, they failed to trigger rejection of GRKO heart allografts. The impairment in CD4-mediated rejection of GRKO hearts appeared to primarily involve the efferent phase of the immune response. This conclusion was based on the findings that GRKO stimulator cells provoked normal CD4 proliferation in vitro and that intentional in vivo challenge of CD4 cells with wild-type donor APC or the adoptive transfer of in vitro primed CD4 T cells failed to provoke acute rejection of GRKO allografts. In contrast, unseparated lymph node cells acutely rejected both GRKO and wild-type hearts with similar time courses, illustrating the existence of both IFN-γ-dependent and IFN-γ-independent mechanisms of acute allograft rejection.

show abstract

An Essential Contribution by IFN-γ to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts

Cited by 84 publications

References 59 publications

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

The Role of CC Chemokine Receptor 5 (CCR5) in Islet Allograft Rejection

Donor IFN-γ Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection

Contact Info

Product

Resources

About