Many of the features of GVHD in experimental animals are shared by infant human marrow recipients with ensuing GVHD, yet whether such infants are at risk of brain growth retardation is unknown. We have documented that GVHD induces brain growth retardation in neonatal rats. In GVHD, many fewer neurons are formed in the postnatally developing rat cerebellum, DNA synthesis per germinal cell is less, and the levels of actin and tubulin, two proteins implicated in mitosis, migration, and growth of neuronal processes, are decreased. We postulate a decrease in the amount of total mRNA as well as in the mRNAs encoding actin and the tubulins in dividing cells. The work proposed here further tests the hypothesis that brain targets suffer, either directly or indirectly, by induction of selective changes in genetic expression in affected brain regions and cells and that these changes can be reversed by alloantiserum treatment. To determine whether such direct, cell-mediated effects occurs, we will further test for lymphoid cells which may have access to cerebellar cells during GVHD. To determine whether non cell-mediated factors such as those elaborated during graft-lymphocyte, host-lymphocyte interaction may affect cerebellar development, we will test for the presence of one such molecule, interleukin I, a monokine, that has access to brain and also influences immune responses in the periphery. Alternatively, altered hormone levels could be responsible for GVHD-induced brain growth retardation. GVHD- and corticosteroid-induced cerebellar growth retardation are somewhat similar. Increased levels of corticosteroids are features of the immune response and GVHD. We will compare the cerebellar effects of exogenously administered corticosteroids (HC) with those of GVHD and assess the effects of GVHD and (HC) on the levels of mRNAs encoding the precursor molecule of ACTH which regulates serum levels of corticosteroids. We will also compare the synthesis of serum corticosteroid binding globulin in these two conditions. Completion of our aims will demonstrate: (1) the effects of a systemic immune disease on gene expression in individual cells in brain and whether GVHD and its termination by alloantiserum can be used to manipulate and thus study gene expression in developing brain; (2) possible innocent bystander molecules and effects; and (3) mechanisms by which GVHD influences free corticosterone levesl, the possible cause of brain growth retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI014663-09
Application #
3125828
Study Section
Pathology A Study Section (PTHA)
Project Start
1987-02-01
Project End
1989-01-31
Budget Start
1987-02-01
Budget End
1989-01-31
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Griffin, W S; Stanley, L C; Ling, C et al. (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86:7611-5
Sparkman, D R; Johnson, S A; Hammon, K M et al. (1987) Isolation of the insoluble straight fibrils of Pick's disease. J Neurol Sci 80:173-84
Griffin, W S; Lonsberry, L M (1987) Graft-versus-host disease: a model for studying the neural regulation of immune function. Transplant Proc 19:1130
Morrison, M R; Griffin, W S (1986) Quantitation and in situ localization of tubulin mRNA in the mammalian nervous system. Ann N Y Acad Sci 466:51-74
Head, J R; Griffin, W S (1985) Functional capacity of solid tissue transplants in the brain: evidence for immunological privilege. Proc R Soc Lond B Biol Sci 224:375-87
Griffin, W S; Morrison, M R (1985) In situ hybridization--visualization and quantitation of genetic expression in mammalian brain. Peptides 6 Suppl 2:89-96
Griffin, W S; Alejos, M A; Cox, E J et al. (1985) The differential distribution of beta tubulin mRNAs in individual mammalian brain cells. J Cell Biochem 27:205-14