Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Guo, Zhong; Wang, Jiaxing; Meng, Lingzhong; Wu, Qiang; Kim, O; Hart, John; He, Gang; Zhou, Ping; Thistlethwaite, J.; Ml, Alegre; Fu, Y.; Newell, K A

doi:10.4049/jimmunol.167.9.4796

Cited by 47 publications

(40 citation statements)

References 27 publications

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“…This result implies that short-term blockade of this pathway with LTbRIg alone is not sufficient to induce prolonged suppression of CD8 + T-cell alloimmunity (24).…”

Section: Introductionmentioning

confidence: 97%

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Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Wang

Gao

Lunsford

et al. 2003

American Journal of Transplantation

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Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8 + T-cell-initiated graft rejection. The (CD4-independent) CD8 + T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4 + T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4-and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8 + T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4-and CD8-dependent T-cell pathways available).

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“…This result implies that short-term blockade of this pathway with LTbRIg alone is not sufficient to induce prolonged suppression of CD8 + T-cell alloimmunity (24).…”

Section: Introductionmentioning

confidence: 97%

“…These include inducible costimulatory molecule ICOS/B7H (12)(13)(14), 4-1BB/4-1BB ligand (4-1BBL) (15)(16)(17)(18)(19)(20), OX40/OX40 ligand (OX40L) (21,22), LIGHT and herpesvirus entry mediator (HVEM) or lymphotoxin b receptor (LTbR), and membrane lymphotoxin (mLT)/LTbR (mLT/LTbR) interactions (23,24).…”

Section: Introductionmentioning

confidence: 99%

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Wang

Gao

Lunsford

et al. 2003

American Journal of Transplantation

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“…In the case of LCMV infection, autoimmune prone mice could be rescued by LT␤R-Ig from a viral shock induced death (26). The effects on lymphocytic choriomeningitis virus-induced CD8 expansion/maturation were paralleled in the ability of LT␤R-Ig or an anti-LT␤ Ab to block intestinal graft rejection in a CD4 cell-deficient setting (27). A precise description of the relative roles of LIGHT and LT in T cell activation and differentiation has not yet emerged.…”

Section: T He Lymphotoxin (Lt)mentioning

confidence: 99%

A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis

Fava

Notidis

Hunt

et al. 2003

The Journal of Immunology

111

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A lymphotoxin-β (LTβ) receptor-Ig fusion protein (LTβR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTβR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTβR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTβR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.

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“…These studies are complicated by the broad cellular distribution of TNF/TNFR SF molecules and the ability of certain receptor/ligand pairs to bind more than one partner with high affinity. We have recently shown that disruption of the TNF/TNFR SF pair lymphotoxin b receptor (LTbR)/membrane lymphotoxin (mLT) inhibited the rejection of intestinal allografts by CD8 + T cells (7). This finding is of particular importance given the observation that although rejection mediated by CD4 + T cells can be inhibited by blockade of the CD28/B7 and/or CD154/CD40 costimulatory pathways, rejection mediated by CD8 + T cells is resistant to the blockade of traditional costimulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

Role of 4-1BB in Allograft Rejection Mediated by CD8+ T Cells

Wang

Guo

Dong

et al. 2003

American Journal of Transplantation

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Blockade of traditional costimulatory molecules fails to inhibit rejection in many models where CD8 + T cells are sufficient to mediate rejection. This observation demonstrates that in many settings CD8 + T cells are not dependent upon CD28 or CD154 signals to mediate rejection. 4-1BB (CD137) has been shown to be an important regulatory molecule for CD8 + T cells in a variety of nontransplant models. Here we show that blocking the 4-1BB pathway significantly inhibited rejection of intestinal allografts by CD8 + but not CD4 + T cells. This effect was associated with significantly decreased expression of the genes encoding TNFa and secondary lymphoid chemokine (SLC) within the spleens of recipient mice. Disruption of the 4-1BB pathway also impaired the priming of alloantigen-specific CD8 + T cells and the accumulation of recipient dendritic cells within the spleen. These data directly demonstrate an important role for 4-1BB in allograft rejection; particularly rejection mediated by CD8 + T cells. Our data suggest that in addition to providing a direct costimulatory signal to T cells, the 4-1BB pathway may regulate other important steps in the immune response such as the migration of T cells and dendritic cells.

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Cutting Edge: Membrane Lymphotoxin Regulates CD8+ T Cell-Mediated Intestinal Allograft Rejection

Cited by 47 publications

References 27 publications

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

A Role for the Lymphotoxin/LIGHT Axis in the Pathogenesis of Murine Collagen-Induced Arthritis

Role of 4-1BB in Allograft Rejection Mediated by CD8+ T Cells

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