Immunopotentiating Role of IFN-γ in Early and Late Stages of Type 1 CD8 Effector Cell-Mediated Tumor Rejection

Immune destruction of the graft renal tubules is an important barrier to the long-term function of clinical renal allografts, but the underlying mechanisms remain obscure. CD103—an integrin conferring specificity for the epithelial cell-restricted ligand, E-cadherin—defines a subset of CD8 effectors that infiltrate the graft tubular epithelium during clinical rejection episodes, predicting a causal role for CD103+CD8+ effectors in tubular injury. In the present study, we used rodent transplant models to directly test this hypothesis. Surprisingly, CD8 cells infiltrating renal allografts undergoing unmodified acute rejection did not express significant levels of CD103. However, we demonstrate that a brief course of cyclosporine A to rat renal allograft recipients promotes progressive accumulation of CD103+CD8+ cells within the graft, concomitant with the development of tubular atrophy and interstitial fibrosis. As in the known clinical scenario, graft-associated CD103+CD8+ cells exhibited a T effector phenotype and were intimately associated with the renal tubular epithelium. Treatment with anti-CD103 mAb dramatically attenuated CD8 infiltration into the renal tubules and tubular injury. Mouse studies documented that CD103 expression is required for efficient destruction of the graft renal tubules by CD8 effectors directed to donor MHC I alloantigens. Taken together, these data document a causal role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation and identify novel targets for therapeutic intervention in this important clinical problem.

Section: Discussionmentioning

confidence: 71%

Critical Role for CD103+CD8+ Effectors in Promoting Tubular Injury following Allogeneic Renal Transplantation

Yuan¹,

El-Asady

Liu

et al. 2005

“…Adoptive transfer of CTL with specificity for another MDP, TRP-2, has been shown to be effective in nontransgenic mice (60). In addition, protective immunity against B16 has been induced by active immunization with TRP-2 180 -188 (31,37,61), gp100 [25][26][27][28][29][30][31][32][33] (31,59), or MART-1 (38). However, our study is the first to examine the antitumor efficacy of HLA-A*0201-restricted peptides that are highly homologous or identical with human melanoma Ags.…”

Section: Discussionmentioning

confidence: 99%

“…Insight has been gained from model tumors expressing Ags such as OVA (31,32), ␤-galactosidase (33), and influenza hemagglutinin (34). These models are based on highly immunogenic Ags that are overtly foreign (31)(32)(33) or are expressed in tissues and at levels that may engender different mechanisms of self-tolerance (35,36) and may not represent optimal models for the evaluation of clinically relevant therapeutic maneuvers. More relevant models for the evaluation of the melanoma-associated Ags TRP-2, gp100, and MART-1 have been based on B16 melanoma (36 -38).…”

mentioning

confidence: 99%

Immune Responses to the HLA-A0201-Restricted Epitopes of Tyrosinase and Glycoprotein 100 Enable Control of Melanoma Outgrowth in HLA-A0201-Transgenic Mice

Mullins

Bullock

Colella

et al. 2001

Many of the Ags recognized by human melanoma-reactive CTL are derived from proteins that are also expressed in melanocytes. The possibility of self-tolerance to these epitopes has led to questions about their utility for antitumor immunotherapy. To investigate the issue, we established a preclinical model based on transgenic mice expressing a recombinant HLA-A*0201 molecule and B16 melanoma transfected to express this molecule. HLA-A*0201-restricted epitopes from the melanocyte differentiation proteins (MDP) tyrosinase and gp100 are expressed in both tumor cells and melanocytes, and the former is associated with self-tolerance. However, adoptive transfer of tyrosinase or gp100-reactive CTL developed from tolerant mice delayed tumor outgrowth, as did immunization with MDP peptide-pulsed dendritic cells. Protection was enhanced by the use of peptide ligands containing conservative substitutions that were cross-reactive with the original Ags. These data establish that CTL populations reactive against MDP-derived self-Ags can be activated to mount effective antitumor immunity and strongly support their continued development for tumor immunotherapy in humans.

“…Tumor-specific CTL effector functions are dependent on IFN-␥ signaling (8,9). IFN-␥ has pleiotropic effects in the tumor microenvironment, including the inhibition of cell proliferation and angiogenesis (10).…”

Section: T Is Well Accepted That Infiltration Of Effector T Cells Imentioning

confidence: 99%

Radiation-Induced IFN-γ Production within the Tumor Microenvironment Influences Antitumor Immunity

Lugade

Sorensen

Gerber

et al. 2008

433

321

Alterations to the tumor microenvironment following localized irradiation may influence the effectiveness of subsequent immunotherapy. The objective of this study was to determine how IFN-γ influences the inflammatory response within this dynamic environment following radiotherapy. B16/OVA melanoma cells were implanted into C57BL/6 (wild-type (WT)) and IFN-γ-deficient (IFN-γ−/−) mice. Seven days after implantation, mice received 15 Gy of localized tumor irradiation and were assessed 7 days later. Irradiation up-regulated the expression of VCAM-1 on the vasculature of tumors grown in WT but not in IFN-γ−/− mice. Levels of the IFN-γ-inducible chemokines MIG and IFN-γ-inducible protein 10 were decreased in irradiated tumors from IFN-γ−/− mice compared with WT. In addition to inducing molecular cues necessary for T cell infiltration, surface MHC class I expression is also up-regulated in response to IFN-γ produced after irradiation. The role of IFN-γ signaling in tumor cells on class I expression was tested using B16/OVA cells engineered to overexpress a dominant negative mutant IFN-γ receptor (B16/OVA/DNM). Following implantation and treatment, expression of surface class I on tumor cells in vivo was increased in B16/OVA, but not in B16/OVA/DNM tumors, suggesting IFN-γ acts directly on tumor cells to induce class I up-regulation. These increases in MHC class I expression correlated with greater levels of activated STAT1. Thus, IFN-γ is instrumental in creating a tumor microenvironment conducive for T cell infiltration and tumor cell target recognition.