Immune deficiency following bone marrow transplantation or in AIDS leaves a patient highly susceptible to life threatening opportunistic infections. Recovery of the immune system, particularly T cell function, is often delayed for up to several years, especially in aged individuals. Thus far, while cytokines have been given clinically to accelerate myeloid recovery, very few agents have been demonstrated to promote multi-lineage immune cell recovery and fewer yet promote thymopoiesis and T cell recovery. Neuroendocrine hormones such as growth hormone (GH) and prolactin (PRL) have been demonstrated to exert pleiotropic effects on the immune system. We have previously demonstrated that GH and PRL promote T cell function and restore thymopoiesis in neuroendocrine hormone-deficient dwarf mice. This proposal will now evaluate the effects of GH and PRL on immune recovery in several BMT models, comparing the effects in both young (less than 10 weeks) and aged (greater than18 months) mice. Use of these mice will allow for the assessment on the role of age on the outcome following BMT. Toward this goal, we have developed 5 specific aims:
Specific Aim 1 will assess the effects of GH and PRL on immune recovery after syngeneic BMT in young and aged mice. Particular emphasis will be given to effects on the thymus and T cell recovery.
Specific Aim 2 will use a thymic organ culture model to determine the mechanism underlying the effects of hormones on the thymus.
Specific Aim 3 will evaluate the effects of GH and PRL in allogeneic BMT models using T cell depleted BMC to ascertain effects on host rejection mechanisms and subsequent engraftment.
Specific Aim 4 will examine the effects of GH and PRL on allogeneic BMT models in which graft-versus-host disease (GVHD) occurs to determine whether GVHD is worsened after hormone treatment. Finally, Specific Aim 5 will use nonmyeloablative BMT models to determine the effects of GH and PRL conditioning on thymic recovery and engraftment of donor-derived cells. All of the Specific Aims will use young and aged mice to ascertain if age significantly impacts hormone responsiveness. Thus far, even though immune reconstitution in the aged remains a significant and growing concern, very few preclinical studies have addressed the role of age and potential use of neuroendocrine hormones to circumvent the hampered immune recovery associated with age. This proposal will thus address both basic science (role of hormones in immune development) and clinically useful (role of age in BMT procedures and use of hormones to promote recovery) issues.
| Redelman, Doug; Welniak, Lisbeth A; Taub, Dennis et al. (2008) Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network. Cell Immunol 252:111-21 |
| Welniak, Lisbeth A; Blazar, Bruce R; Murphy, William J (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139-70 |
| Blazar, Bruce R; Murphy, William J (2005) Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD). Philos Trans R Soc Lond B Biol Sci 360:1747-67 |
| Dorshkind, Kenneth; Welniak, Lisbeth; Gault, Ruth A et al. (2003) Effects of housing on the thymic deficiency in dwarf mice and its reversal by growth hormone administration. Clin Immunol 109:197-202 |
