PMID- 12063030
OWN - NLM
STAT- MEDLINE
DCOM- 20020710
LR  - 20191025
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 30
IP  - 6
DP  - 2002 Jun
TI  - Alloreactivity following in utero transplantation of cytokine-stimulated 
      hematopoietic stem cells: the role of recipient CD4(-) cells.
PG  - 617-24
AB  - OBJECTIVE: We have previously reported immunity to donor antigens following in 
      utero transplantation (IUT) of cytokine-stimulated allogeneic hematopoietic stem 
      cells (sca(+)/lin(-)) (day 9 of gestation). Transplanted mice showed accelerated 
      rejection of donor skin grafts and high anti-donor cytotoxic response, a finding 
      not seen in the control mice. This was accompanied by an enhancement of Th1 over 
      Th2 cytokine production and persistent donor microchimerism. In order to assess 
      the role of the thymus in allograft rejection, prenatal transplants were 
      performed under similar experimental conditions at a later gestational age, when 
      the thymus is more developed (day 13). MATERIALS AND METHODS: Cytokine-stimulated 
      stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF)-purified 
      sca(+)/lin(-) cells of C57BL/6 (H-2b, 1E(+)) background were injected into 
      MHC-mismatched BALB/c (H-2d, 1E(-)) fetal mouse recipients at day 13 of 
      gestation. Chimerism was determined by highly sensitive (0.001%) semiquantitative 
      polymerase chain reaction (PCR). Mixed lymphocyte reaction (MLR) and cytotoxic 
      T-cell assay (CTL) were used to evaluate tolerance vs immunity. Cytokine levels 
      were quantified in MLR supernatants using ELISA assay. The percent of T cells was 
      determined by flow cytometry (FACS) and CD4/CD8 ratio calculated. Postnatal 
      boosts (transplants without conditioning) were performed at 6 months of age to 
      enhance donor chimerism and test the degree of tolerance. RESULTS: When assayed 
      at 4 months of age, donor-type cells were not detected in the spleen or in the 
      peripheral blood of BALB/c mice inoculated with C57BL/6 sca(+)/lin(-) cells. 
      Transplanted but not control animals demonstrated high anti-donor MLR but not CTL 
      responses. The increase of MLR reactivity was correlated with high levels of 
      IL-2. Furthermore, transplanted mice showed higher resistance to postnatal boosts 
      with allogeneic bone marrow (BM) cells, when compared to the control mice. The 
      later resistance was accompanied by the expansion of host-type CD4 cells. 
      CONCLUSION: These data demonstrate that transplantation of cytokine-stimulated 
      sca(+)/lin(-) allogeneic cells at 13 days of fetal development leads to the 
      allosensitization, characterized by an enhancement of MLR alloreactivity and by 
      the rejection of postnatal boosts (transplants without conditioning). Host-type 
      CD4 cells might play a central role in this rejection. These findings indicate 
      that the late injection of allogeneic cells may result in the development of 
      allosensitization with subsequent donor graft rejection. Precise conditions for 
      the development of tolerance must be established before prenatal transplants in 
      humans with conditions other than SCID can be done.
FAU - Sefrioui, Hassan
AU  - Sefrioui H
AD  - Department of Medicine and Pediatrics, University of California, San Diego, USA.
FAU - Donahue, Jody
AU  - Donahue J
FAU - Srivastava, Anand Shanker
AU  - Srivastava AS
FAU - Gilpin, Elizabeth
AU  - Gilpin E
FAU - Lee, Tzong-Hae
AU  - Lee TH
FAU - Carrier, Ewa
AU  - Carrier E
LA  - eng
GR  - 5R01-DK57524/DK/NIDDK NIH HHS/United States
GR  - K08-HL03603/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, CD34)
RN  - 0 (Cytokines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Stem Cell Factor)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
SB  - IM
MH  - Animals
MH  - Antigens, CD/analysis
MH  - Antigens, CD34/analysis
MH  - Cytokines/analysis
MH  - Cytotoxicity, Immunologic
MH  - Female
MH  - Gestational Age
MH  - Granulocyte Colony-Stimulating Factor/pharmacology
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - Killer Cells, Natural/immunology
MH  - Lymphocyte Culture Test, Mixed
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Pregnancy
MH  - Recombinant Proteins/pharmacology
MH  - Stem Cell Factor/pharmacology
MH  - T-Lymphocytes, Cytotoxic/immunology
EDAT- 2002/06/14 10:00
MHDA- 2002/07/12 10:01
CRDT- 2002/06/14 10:00
PHST- 2002/06/14 10:00 [pubmed]
PHST- 2002/07/12 10:01 [medline]
PHST- 2002/06/14 10:00 [entrez]
AID - S0301472X02008032 [pii]
AID - 10.1016/s0301-472x(02)00803-2 [doi]
PST - ppublish
SO  - Exp Hematol. 2002 Jun;30(6):617-24. doi: 10.1016/s0301-472x(02)00803-2.