RESUMO
Acute graft-versus-host disease (GVHD) is still a major hurdle for successful bone marrow transplantation (BMT). Although many immunosuppressive drugs are available, none of them alone or in combination are able to completely abolish acute GVHD. The lifelong immunosuppression profoundly reduces the quality of life of BMT recipients. Therefore, new therapeutic approaches are needed. We previously reported that, in an acute GVHD model using SCID mice as recipient, incubating donor spleen cells with antibodies directed at CD49d and CD62L could significantly delay the occurrence of acute GVHD. To test the potential usefulness of this treatment in BMT, we examined this therapeutic protocol in a mouse BMT model. The present mouse BMT study confirmed our previous results that incubation of donor cells with antibodies directed at CD49d and CD62L prior to infusion into the recipient can effectively delay acute GVHD, allowing the recipients to recover from the side effects of total body irradiation. This one-time treatment is easy and simple and may be modified for clinical usage.
Assuntos
Transplante de Medula Óssea/imunologia , Facilitação Imunológica de Enxerto/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Integrina alfa4/imunologia , Selectina L/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Masculino , Camundongos , Fatores de TempoRESUMO
Acute graft-versus-host disease (GVHD) involves mainly skin, liver and intestines. Other organs such as heart, muscle and central nervous system are seldom affected, although their parenchymal cells also express alloantigens, such as MHC class I antigens. The mechanism of this selective involvement of distinct organs in acute GVHD is not well understood. We postulated that it might be related to the selective migration of activated alloreactive T cells. Indeed, T cell infiltration, revealed by examination of serial samples using flow cytometry and immunohistology, occurred early and continuously in the target organs such as the liver, but not in a non-target organ, the heart, in a murine acute GVHD model. Since T cell migration is largely controlled by the expression of chemokine and chemokine receptors, we investigated the chemokine spectrum in target/non-target organs of mice with acute GVHD. We found that in the spleen and liver MIP-1alpha, MIP-2 and Mig were the predominant chemokines expressed. In another target organ, the skin, MIP-1alpha, MIP-2, MCP-1 and MCP-3 were all highly expressed. In a non-target organ of acute GVHD, the heart, the predominant chemokines expressed were MCP-1 and MCP-3. This distinct pattern of chemokine expression in these organs may contribute to the preferential recruitment of inflammatory cells into the liver and skin, but not into the heart, in acute GVHD.
Assuntos
Quimiocinas/análise , Quimiotaxia de Leucócito/fisiologia , Citocinas , Doença Enxerto-Hospedeiro/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Linfócitos T/fisiologia , Doença Aguda , Animais , Quimiocina CCL2/análise , Quimiocina CCL2/sangue , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL7 , Quimiocina CXCL2 , Quimiocina CXCL9 , Quimiocinas/sangue , Quimiocinas CXC/análise , Quimiocinas CXC/sangue , Doença Enxerto-Hospedeiro/imunologia , Fígado/química , Proteínas Inflamatórias de Macrófagos/análise , Proteínas Inflamatórias de Macrófagos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quimioatraentes de Monócitos/análise , Proteínas Quimioatraentes de Monócitos/sangue , Miocárdio/química , Especificidade de Órgãos , Pele/química , Baço/químicaRESUMO
L-selectin, LFA-1 and alpha(4) integrins play important roles in the homing of naïve T cells into peripheral lymphoid tissues. L-selectin- or LFA-1-deficient lymphocytes cannot effectively home to lymph nodes (LN), and antibody blockade of alpha(4) integrins also hinders lymphocytes homing. The present study was initiated to explore whether it is feasible to ameliorate acute graft-versus-host disease (aGVHD) by modulating the homing process of donor cells in the recipient in a mouse model. Using a fluorescence labeling method, we found that two monoclonal antibodies directed at L-selectin and alpha(4) integrins, respectively, when used in combination, could delay half of the donor C57BL/6J mouse spleen cells homing into the LN of recipient BALB/c mouse 15 h after injection. Spleen cells (1 x 10(7)) derived from C57BL/6J (H-2(b)) mice were injected into each C.B-17 SCID recipient mouse (H-2(d)) with or without prior incubation with 10 microg each of the two antibodies. T cell repopulation in the blood was observed in both groups of mice at a comparable level 14 days after injection of the donor cells. Eight control mice started to show aGVHD signs 7 - 14 days after the injection, and all died by day 31. However, among the ten mice that received the antibody-treated donor cells, two died before day 29, four survived between 36 and 78 days, and the remaining four survived more than 150 days, with two of them aGVHD free. It is apparent that the temporarily reduced lymphocyte homing into LN reduced the alloreactivity of the donor T cells, thus providing a simple way of modifying aGVHD. This novel approach may shed light on the prevention of aGVHD associated with clinical bone marrow transplantation.