Effects of T Cell Frequency and Graft Size on Transplant Outcome in Mice

Self Cite

Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.H-2bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25+ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2bm12 heart grafts. Similarly, reconstitution of B6.Rag−/− recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2bm12 heart grafts only if CD25+ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25+ regulatory cells that restrict the clonal expansion of alloreactive T cells.

Section: Figurementioning

confidence: 65%

“…Priming of donor-specific T cells to IFN-␥-producing cells was quantified by ELISPOT assays as previously described (8,10). Briefly, ELISA spot plates (Unifilter 350; Whatman) were coated with 2 g/ml IFN-␥-specific mAb and incubated overnight at 4°C.…”

Section: Elispot Assaysmentioning

confidence: 99%

Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells

Schenk¹,

Kish²,

He³

et al. 2005

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“…This strategy, however, completely abrogated rejection of the grafts in MT Ϫ/Ϫ /CCR5 Ϫ/Ϫ and MT Ϫ/Ϫ recipients (T. Nozaki, unpublished results). Studies from several laboratories have indicated the need for a threshold frequency of donor-reactive effector T cells to reject allografts (35,36). The rejection of allografts in the MT Ϫ/Ϫ /CCR5 Ϫ/Ϫ recipients suggests that the low number of CD8 T cells primed in CCR5-deficient recipients eventually reaches the necessary threshold to reject the grafts.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Nozaki

Amano

Bickerstaff

et al. 2007

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Rejected MHC-mismatched cardiac allografts in CCR5−/− recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5−/− recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5−/− (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-γ, whereas CD4 T cells producing IL-4 were increased in CCR5−/− recipients. Numbers of donor-reactive CD8 T cells producing IFN-γ were reduced 60% in CCR5−/− recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5−/− allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1−/− recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5−/− recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in μMT−/−/CCR5−/− recipients. These results indicate that the donor-specific Ab produced in CCR5−/− heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.

“…Male donors only differ from female recipients of the same strain by a single minor Ag, HY. Even skin grafts, normally regarded as highly immunogenic, are not rejected in most HY-mismatch combinations, except in mice of the H-2 b haplotype (30, 31), while heart grafts are not rejected at all (32). Whether male kidney grafts are rejected by female recipients is previously unknown.…”

Section: Acceleration Of Rejection Kidneys From a Single Minor Ag-mismentioning

confidence: 99%

Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection

Moxham¹,

Karegli²,

Phillips³

et al. 2008

Homeostatic proliferation is a normal physiological process triggered by lymphopenia to maintain a constant level of T cells. It becomes the predominant source of new T cells in adulthood after thymus regression. T cells that have undergone homeostatic proliferation acquire the memory phenotype, cause autoimmune disease, and are resistant to tolerance induction protocols. Transplantation is a rare example in which lymphopenia is deliberately induced for its immunosuppressive effect. However, it is not known whether the homeostatic proliferation that follows will have the opposite effect and accelerate rejection. We show that T cells that have undergone homeostatic proliferation acquire a memory phenotype, spontaneously skews toward the Th1 phenotype, even in the absence of antigenic stimulus. Interestingly, in contrast, the percentage of Foxp3+ regulatory T cells increased by 28-fold following homeostatic proliferation. Using a mouse life-sustaining kidney transplant model, we showed that T cells that have gone through homeostatic proliferation in lymphopenic hosts transformed chronic rejection to acute rejection of a single MHC class II-mismatched kidney allograft. T cells that have undergone homeostatic proliferation consistently cause reliable rejection even when bona fide memory T cells cannot. These functional changes are long-lasting and not restricted to the acute phase of homeostatic proliferation. Our findings have important implications for tolerance induction or graft-prolonging protocols involving leukocyte depletion such as irradiation bone marrow chimera, T cell-depleting Abs, and lymphopenia induced by infections such as CMV and HIV.