https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1600-6135.2003.00246.x

Development of a Novel Transgenic Mouse for the Study of Interactions Between CD4 and CD8 T Cells During Graft Rejection

Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions.

Maneuvers that interfere with signals 1, 2, 3, or Ag processing can result in indefinite allograft survival. However, they are not applicable to all tissues, strains, or species, suggesting that there are additional levels of immune regulation. We hypothesized that secondary lymphoid organs are important for interactions among lymphocytes, alloantigen, and immunosuppressants that lead to tolerance. To explore this, cardiac allografts were performed with a tolerogenic immunosuppressive regimen. Concurrent administration of anti-L-selectin (CD62L) Ab, which prevents lymph node homing, prevents indefinite allograft survival and tolerance. Anti-CD62L Ab is not costimulatory, and Fab and F(ab′)2 anti-CD62L have similar activities. Flow cytometry and histologic examination show that Ab shifts T cells away from lymph nodes and into spleen, peripheral blood, and graft. Tolerance is not induced in CD62L−/− mice, and adoptive transfer of CD62L−/−, but not CD62L+/+, T cells prevents tolerization in wild-type recipients. FTY720, an immunosuppressant that promotes chemokine-dependent, but CD62L-independent, lymph node homing, reverses the Ab effect. Blockade of other homing receptors also prevents tolerization. These results indicate that T lymphocytes use CD62L-dependent migration for alloantigen-specific tolerance, and suggest that lymph nodes or other lymphoid tissues are an important site for peripheral tolerization to alloantigen.

/pdf/l-selectin-dependent-lymphoid-occupancy-is-required-to-3j4wrdra39.pdf

L-selectin-dependent lymphoid occupancy is required to induce alloantigen-specific tolerance.

BACKGROUND: Acute rejection of allografts remains a significant problem in clinical transplantation, and the fundamental mechanism underlying this rejection are as yet only poorly elucidated. Recently, DNA microarrays have come into use for the study of gene expression profiles, and we have taken advantage of this new technology to investigate acute rejection. We compared mRNA profiles in murine cardiac allografts with isografts using DNA microarrays with probe sets corresponding to more than 11,000 mice genes. METHODS: We screened for gene expression changes in murine cardiac allografts between fully incompatible mice strains (BALB/c H2d to C3H/He H2k) using a DNA microarray. The heart was heterotopically transplanted. Allografts (BALB/c to C3H/He) were removed on days 1, 3, and 5. As a control, isografts (C3H/He to C3H/He) harvested on days 1, 3, and 5 and native hearts of both strain mice (C3H/He and BALB/c) were obtained. RESULTS: On day 5, interferon-gamma (IFN-gamma) and many IFN-gamma-inducible genes were profoundly induced in the allograft relative to isograft. Monokine induced by IFN-gamma was most profoundly induced followed by inducibly expressed GTPase and Lmp-2. IFN-gamma was also profoundly induced. The induction was detectable from day 3. In contrast, genes regulated by other cytokines exhibited only modest changes. CONCLUSION: IFN-gamma-inducible genes are specifically up-regulated in murine cardiac allografts, suggesting that signaling mediated by IFN-gamma may play an important role in the late phase of acute rejection in vivo.

A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis.

The role of passenger leukocytes in determining the outcome after transplantation is complex. In some settings, donor-derived passenger leukocytes can initiate graft rejection, whereas in others they contribute to graft acceptance. Both donor and recipient factors contribute to this potential dual role. Understanding the interaction between passenger leukocytes and the recipient's immune system, particularly after liver transplantation, may provide important clues for developing novel strategies for inducing specific unresponsiveness to donor alloantigens.

Passenger leukocytes and microchimerism: what role in tolerance induction?

Background. An adoptive transfer system was used to study the fate of alloreactive CD8 + H-2K b -specific TCR transgenic (DES + ) T cells in vivo after transplantation. Methods. A trace population of 2.0×10 6 CD8 + DES + T cells were adoptively transferred into syngeneic CBA.Ca (H-2 k ) mice 24 hr before transplantation of an H-2K b+ or H-2K b- cardiac allograft. Results. H-2K b specific T cells proliferated and produced interleukin-2 and interferon-y in response to H-2K b+ , but not H-2K b- cardiac allografts. CD8 + DES + T cells that infiltrated the H-2K b+ cardiac allografts developed a distinct cell surface and cytokine phenotype compared with the CD8 + DES + T cells that remained in the periphery. H-2K b -specific graft infiltrating T cells (a) underwent a larger number of cell divisions (>=3), (b) increased in size, (c) up-regulated CD69, and (d) down-regulated CD62L. Conclusions. These results demonstrate that alloantigen-specific T cells can be monitored in vivo during the immune response to an allograft and that the fate of CD8 + T cells specific for the allogeneic class I molecules expressed by the graft is different between cells in the periphery and those that infiltrate the graft.

Visualization of the in vivo generation of donor antigen-specific effector CD8+ T cells during mouse cardiac allograft rejection: in vivo effector CD8+ T cell generation during allograft rejection.

In vivo differentiation of alloreactive CD8+ T cells after murine cardiac allograft transplantation.

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Visualization of the in vivo generation of donor antigen-specific effector CD8+ T cells during mouse cardiac allograft rejection: in vivo effector CD8+ T cell generation during allograft rejection.

In vivo differentiation of alloreactive CD8+ T cells after murine cardiac allograft transplantation.