Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease.

Abstract

Acute graft-vs-host disease (GVHD) is thought to be mediated by alloreactive T cells with a type 1 cytokine phenotype. To prevent the development of acute GVHD, we have successfully polarized mature donor T cells toward a type 2 cytokine phenotype ex-vivo by incubating them with murine rIL-4 in a primary MLC. Polarized type 2 T cells were then transplanted with T cell-depleted bone marrow cells into irradiated recipients across either MHC class II (bm12-->C57BL/6) or class I (bm1-->C57BL/6) barriers, and the intensity of GVHD was measured by assessment of several in vitro and in vivo parameters. The injection of polarized type 2 T cells abrogated the mitogen-induced production of IFN-gamma by splenocytes from transplanted hosts on day 13 after bone marrow transplantation (BMT). Injection of polarized type 2 T cells failed to induce secretion of the effector phase cytokine TNF-alpha by splenocytes stimulated with LPS both in vitro and in vivo, and survival of transplanted mice after i.v. injection with LPS was significantly improved. Furthermore, cell-mixing experiments revealed that polarized type 2 T cells were able to inhibit type 1 cytokine responses induced by naive T cells after BMT. These data demonstrate that both polarized CD4+ and CD8+ type 2 alloreactive donor T cells can be generated in vitro from mature T cell populations. These cells function in vivo to inhibit type 1 T cell responses, and such inhibition attenuates the systemic morbidity of GVHD after BMT across both MHC class II or class I barriers in mice.

Comparison of the effect of DLI according to cell sources in relapsed AML after allogeneic stem cell transplantation

“…This leads to the presentation of self-peptides and Th2 polarization in the donor [ 16 , 17 ]. Since donor Th2 cells are less likely to induce aGVHD, the mobilization by G-CSF have been associated with reduced severity of aGVHD [ 16 , 18 , 19 ]. In line with such findings, patients who underwent G-DLI showed less grades III-IV aGVHD after DLI (Table 2 ).…”

Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models

“…Th1 cytokines exert immune activation, enhance the activation and recruitment of macrophages and B cells, and promote cytotoxic T-cell proliferation to induce acute GVHD. However, Th2 cytokines are associated with immunologic tolerance and reduce the production of causative agents of acute GVHD ( 42 ). To investigate whether this shift was maintained in recipients after administration of MEXs in an allo-HSCT animal model, we further analyzed the Th1 cytokines TNF-α and Th2 cytokines IL-5 production of splenocytes from recipients 14 days after transplantation.…”

Reacción de ingerto versus huésped: de la comprensión a la utilización de un fenómeno biológico

“…El perfil de citoquinas que ellos secreten en respuesta a un estimulo antigénico determina el carácter de la respuesta inmune (50). En general, la estimulación de células tipo Th1 (IL-2, IFNy), que coincide con las manifestaciones agudas de la ElvH (51), desencadena una respuesta inmune mediada por células, que en el caso de la ElvH se traduce en la activación de otras células efectoras del injerto e inclusive del huésped, tales como mononucleares, células asesinas naturales (NK) y macrófagos; ellas a su vez sintetizan IL-1 y TNFa lo que prolonga la respuesta inflamatoria y el daño tisular. Por ejemplo, el TNFa es un mediador en los procesos inflamatorios y posiblemente tiene una función preponderante en la generación de las lesiones cutáneas e intestinales, características de la ElvH (52), ya que en los pacientes con enfermedad activa se ha demostrado la presencia de ARN mensajero de TNFa, al igual que secreción de dicha citoquina en las lesiones cutáneas.…”