PMID- 9311705
OWN - NLM
STAT- MEDLINE
DCOM- 19971014
LR  - 20190713
IS  - 0041-1337 (Print)
IS  - 0041-1337 (Linking)
VI  - 64
IP  - 5
DP  - 1997 Sep 15
TI  - Effects of leflunomide and deoxyspergualin in the guinea pig-->rat cardiac model 
      of delayed xenograft rejection: suppression of B cell and C-C chemokine responses 
      but not induction of macrophage lectin.
PG  - 696-704
AB  - BACKGROUND: If complement (C) activation is prevented or the host is C depleted, 
      discordant vascularized xenografts undergo delayed xenograft rejection (DXR), 
      characterized by graft infiltration by macrophages (MO) and natural killer (NK) 
      cells, endothelial cell activation, and widespread fibrin deposition. Given a 
      lack of effect of T cell-directed therapies on development of DXR, we evaluated 
      two novel agents, 15-deoxyspergualin (DSG) and leflunomide (LEF), with reported 
      anti-B-cell and/or anti-MO actions. METHODS: DSG and LEF were administered to 
      C-depleted, splenectomized rat recipients of guinea pig cardiac xenografts, and 
      their effects on graft survival and production of anti-guinea pig antibodies were 
      determined. Serial intragraft events were studied by immunohistology using 
      monoclonal antibodies to rat leukocytes, cytokines, and novel proteins, including 
      rat MO lectin, which in other systems is important to MO binding, activation, and 
      target cell killing. RESULTS: Median graft survival was 62 hr in cobra venom 
      factor (CVF)-treated controls versus 108 hr (DSG), 129 hr (LEF), and 120 hr (DSG 
      and LEF; all groups P<0.01 vs. CVF alone). LEF and DSG each decreased 
      (immunoglobulin M [IgM]) or abrogated (IgG) posttransplant production of 
      anti-guinea pig antibodies. Immunohistologic studies showed that each agent also 
      inhibited graft infiltration by NK and T cells, and expression of various 
      cytokines, including the chemokine monocyte chemoattractant protein-1 (MCP-1), 
      but did not affect the tempo or extent of MO infiltration. Consistent with this, 
      the rapid induction of MO lectin postxenografting, and induction of MO lectin by 
      rat MO exposed to guinea pig cells in vitro, were unaffected by therapy with DSG 
      and/or LEF. CONCLUSIONS: LEF or DSG along with CVF can result in the longest 
      prolongation of xenograft survival yet reported in this model, in conjunction 
      with a dampening of host mononuclear cell responses, including suppression of B 
      cell activation. However, the persistent influx of MO in this model, despite lack 
      of C-, Fc receptor- or apparent chemokine-dependent mechanisms, suggests the 
      presence of additional mechanisms for cell recruitment and activation. It was of 
      importance that, in this regard, although MO depletion is technically difficult 
      and can lead to undesired effects, the demonstration of rapid MO lectin induction 
      postxenografting indicates opportunities for blockade of MO recruitment and 
      functions during DXR by use of anti-MO lectin monoclonal antibodies or 
      administration of competing sugars.
FAU - Hancock, W W
AU  - Hancock WW
AD  - Sandoz Center for Immunobiology and Department of Pathology, Beth Israel 
      Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, 
      USA.
FAU - Miyatake, T
AU  - Miyatake T
FAU - Koyamada, N
AU  - Koyamada N
FAU - Kut, J P
AU  - Kut JP
FAU - Soares, M
AU  - Soares M
FAU - Russell, M E
AU  - Russell ME
FAU - Bach, F H
AU  - Bach FH
FAU - Sayegh, M H
AU  - Sayegh MH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (Antibodies, Anti-Idiotypic)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (Guanidines)
RN  - 0 (Immunoglobulin M)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Isoxazoles)
RN  - 0 (Lectins)
RN  - 0 (anti-IgM)
RN  - 9007-36-7 (Complement System Proteins)
RN  - G162GK9U4W (Leflunomide)
RN  - UJ0ZJ76DO9 (gusperimus)
SB  - IM
EIN - Transplantation 1997 Oct 27;64(8):1225
MH  - Animals
MH  - Antibodies, Anti-Idiotypic/blood
MH  - Antibodies, Monoclonal/immunology
MH  - Antibody Formation
MH  - B-Lymphocytes/drug effects/immunology
MH  - Chemokine CCL2/biosynthesis
MH  - Chemokines/pharmacology
MH  - Complement System Proteins/immunology
MH  - Graft Rejection/prevention & control
MH  - Graft Survival/physiology
MH  - Guanidines/*pharmacology/therapeutic use
MH  - Guinea Pigs
MH  - Heart Transplantation/*immunology
MH  - Immunoglobulin M/immunology
MH  - Immunosuppressive Agents/*pharmacology/therapeutic use
MH  - Isoxazoles/*pharmacology/therapeutic use
MH  - Lectins/biosynthesis/immunology
MH  - Leflunomide
MH  - Macrophage Activation/drug effects
MH  - Macrophages/chemistry/physiology
MH  - Male
MH  - Rats
MH  - Rats, Inbred BN
MH  - Rats, Inbred Lew
MH  - Rats, Sprague-Dawley
MH  - Transplantation, Heterologous/*immunology
MH  - Transplantation, Homologous/immunology
EDAT- 1997/10/06 00:00
MHDA- 1997/10/06 00:01
CRDT- 1997/10/06 00:00
PHST- 1997/10/06 00:00 [pubmed]
PHST- 1997/10/06 00:01 [medline]
PHST- 1997/10/06 00:00 [entrez]
AID - 10.1097/00007890-199709150-00006 [doi]
PST - ppublish
SO  - Transplantation. 1997 Sep 15;64(5):696-704. doi: 
      10.1097/00007890-199709150-00006.