C Blackwell Munksgaard 2004
Copyright American Journal of Transplantation 2004; 4: 1756–1761
Blackwell Munksgaard
doi: 10.1111/j.1600-6143.2004.00589.x
Treatment with Anti-MHC-Class-II Antibody Postpones
Kidney Allograft Rejection in Primates but Increases
the Risk of CMV Activation
Margreet Jonker a, ∗ , Jan Ringersb , Eva-Maria
Kuhna,c , Bert ‘t Harta and Roland Foulkesd
a
Biomedical Primate Research Centre, Rijswijk, The
Netherlands,
b
Department of Surgery, Leiden University Medical
Center, Leiden, The Netherlands,
c
Intervet, Boxmeer, the Netherlands and d Celltech,
Slough, UK
∗Corresponding author: Margreet Jonker, jonker@bprc.nl
Treatment of kidney graft recipients with antibodies
that may specifically suppress the anti-donor response
would be an ideal situation to prevent graft rejection.
MHC class-II-specific antibodies and, in particular, DR
specific antibodies have often been proposed as treatment to prevent antigen presentation, and thus graft
destruction. Here we report an attempt to prevent
graft rejection using a humanized MHC class-II-specific
monoclonal antibody CDP855 in a cynomolgus monkey kidney graft model. A modest delay in graft rejection was observed when the antibody was given
only on days 0, 1 and 2 after transplantation. Unexpectedly 50% of the animals succumbed of a viral infection, most likely CMV in two of three cases, prior to
graft rejection in the first week post-transplantation.
We speculate that the antibody treatment triggered
CMV activation, possibly as a consequence of the activation of factors such as NF-j b by the interaction of
the antibody and its target cells.
Key words: CMV, kidney transplantation, MHC-class II
antibody
Received 7 April 2004, revised and accepted for publication 17 June 2004
suppression, preferably to be given only around the time
of transplantation. The most promising approaches in nonhuman primates have been rigorous T-cell depletion combined with other immunosuppression (1–3) and blockade
of co-stimulation (4). Another approach that might be additive to these approaches is to specifically block the APC-Tcell interaction by using MHC class-II-specific antibodies. It
has been shown in rodents (5–11), as well as in monkeys
(12–14) that anti-MHC-class-II antibodies can exert an immunosuppressive effect both in transplantation as well as
in auto immune models (15). However, also serious adverse effects have been reported to occur after in vivo administration of anti-class-II-antibodies in primates (12,13)
and rats (5). These consisted of acute intravascular coagulation, which was dose dependent, and acute shock-like
signs resembling a cytokine release syndrome (8,12,13).
In this study we investigated the safety and efficacy of
CDP855, a humanized, IgG4 version of the murine L243
antibody in a cynomolgus monkey kidney allograft model.
Materials and Methods
Animals
Naive, captive-bred 4–6 kg cynomolgus monkeys (Macaca fascicularis) were
purchased from a commercial breeding station and housed at the Biomedical Primate Research Centre. All procedures were performed in accordance
with guidelines of the Animal Care and Use Committee installed by Dutch
law. All animals were typed for Mafa-A, B and DR antigens by serology (16).
Disparity for DR locus antigens was confirmed by DRB typing. Recipients
were disparate for at least one Mafa-DR antigen and at least one Mafa-A
and -B antigen with the donor. The recipient–donor pairs were compatible
for ABO-antigens (17). In addition, the stimulation index of the one-way
mixed lymphocyte reaction of the recipient cells directed against the donor
antigens was positive (>3, see below).
Introduction
Antibody and treatment
In the recent years an increasing number of immunosuppressive drugs have become available for the prevention
of graft rejection. This has improved graft survival. Unfortunately, the routinely used drugs have serious side effects, which cause morbidity and do not prevent late graft
failure due to chronic vascular pathology. This has stimulated in recent years the search for rejection therapies
that will allow graft function with a minimum of immuno-
In the pre-transplantation safety experiments, the murine DR specific antibodies were used: L243(IgG2a) (18). The Fab 2 fragments, as well as humanized versions of this MHC-DR specific antibody, L235E (chimeric human
IgG1) and CDP855 (chimeric human IgG4) were used for safety assessment.
CDP855 was used in the transplantation study and was given intravenous
(IV) over a period of 60 min. On the day of transplantation (day 0) the total
dose of 10 mg/kg of CDP855 was administered just before the reperfusion
of the transplanted kidney. On days 1 and 2 the test substance was given
IV over a period of 60 min. The animals were sedated for dosing using
ketamine (±10 mg/kg) on days 1 and 2.
1756
Anti-Class-II Treatment in Kidney Transplantation
Plasma levels of CDP855 were not measured in the animals in this study.
However, PK studies performed in healthy animals following three consecutive daily doses of 10 mg/kg CDP855 showed that at this dose the 24-h
trough levels were around 1 lg/mL. This level is most likely sufficient to
block the DR molecules present in the recipients for a short period.
The antibodies used were: FN18/FITC (CD3, BPRC), Leu-3A/PE (CD4, BD),
Leu-2A/PE (CD8, BD), HLA-DR/PE (BD) and Leu-16/PE (CD20, BD). FACS
Lysing Solution (BD) was added according to the instructions of the manufacturer. Flow cytometry was performed on the stained cells with forward
and perpendicular light scatter gates set on the lymphocyte fraction. Data
were stored on discs and subsequently analyzed using the BD FACScanTM
program. For analysis, the unstained control cell population was used for
quadrant marker placement.
Kidney transplantation
Heterotopic kidney allotransplantation with bilateral nephrectomy was performed as described previously (19,20). The clinical condition of the animals
was monitored by daily visual inspection and by frequent hematological
and clinical chemistry blood values determined in a local clinical laboratory
(SSDZ, Delft). Transplant rejection was monitored by serum urea and creatinine. Rejection was not treated. When serum creatinine was >1000 lmol/L
or when the clinical condition deteriorated, the animals were euthanized
and necropsy was performed. For histological examination, tissues from
the necropsy were formalin-fixed and sections were stained with hematoxylin and eosin (H&E), periodic acid Schiff and a silver impregnation stain
(Jones). Histomorphological evaluation of allograft rejection was performed
according to the Banff classification (21). The Mann-Whitney U test was
used as statistical analysis for the graft survival.
CMV IgM and IgG levels were determined by ELISA by a local clinical laboratory (SSDZ, Delft). A human CMV negative reference serum was used as
control. A ratio between the OD of the monkey serum and the reference
serum was calculated, and if this ratio was higher than 1.1, the monkey
was considered to be CMV antibody positive and thus a potential carrier of
CMV.
Results
In vitro effects in monkeys
To test the capacity of CDP855 to block the alloresponse
in monkeys, its inhibitory effects were determined in
mixed lymphocyte cultures of rhesus, cynomolgus monkeys and in human cultures. Eight MLR positive responder–
stimulator cell combinations were tested for each species
in two independent experiments per species. Maximal inhibition of the MLR was observed at concentrations of
1000 ng/mL or higher for all three species. The level of
inhibition was slightly higher in the human cultures as compared to the monkey cultures (Figure 1), but this was not
significant. The IgG1 form of the antibody (L235E) and
the Fab 2 fragments were equally inhibitory (results not
shown).
Immunological determinations
Mixed lymphocyte reactions were performed to evaluate the inhibitory effects of the antibody preparations, and were performed between prospective donor and recipient animals to select MLR positive combinations. Peripheral blood mononuclear cells (PBMC) were obtained using lymphocyte
separation medium (LSM; ICN Biomedical, Aurora, OH). A total of 105 responder PBMC were co-cultured in 96-well round-bottom plates with 105
irradiated (30 Gy) stimulator PBMC in 150 lL RPMI1640 medium supplemented with 25 mM Hepes, 2 mM L-glutamine, 10% heat inactivated
fetal calf serum, 20 lM 2-mercaptoethanol, 100 U/mL penicillium and
200 lg/mL streptomycin (all obtained from Invitrogen, Breda, the Netherlands). The antibodies were added to the cultures at the concentrations
indicated in the results section. The cultures were incubated at 37◦ C in 5%
CO2 for 5 days, the last 20 h in the presence of 0.5 lCi 3H-thymidine in
50 lL. The cells were harvested on filters and radioactivity was measured
in a matrix 9600 beta counter (Packard, Meridan, CT).
Safety aspects in monkeys
MHC class-II-specific monoclonal antibodies have been reported to cause serious side effects. Although such antibodies have been administered without problems in many
Subset analyses were performed using a whole blood assay and analysis
by flow cytometry using a FACScan (Becton Dickinson (BD), Immunocytometric Systems, San Jose, CA). All procedures were performed at 4◦ C.
100
Rhesus monkey
Human
Cynomolgus
90
80
% inhibition
70
Figure 1: Inhibition of MLR of human
cells (open circles), rhesus monkey
cells (open triangles) and cynomolgus monkey cells (closed symbols).
0% inhibition: no antibody added to the
cultures. Inhibition percentage is 100 −
(blocked response/medium response
× 100).
60
50
40
30
20
10
0
1
American Journal of Transplantation 2004; 4: 1756–1761
10
100
1000
10000
100000
CDP855 concentration in ng/ml
1757
Jonker et al.
studies, some antibodies may cause intravascular coagulation, most likely caused by direct stimulation of the vascular
endothelium (12,13). CDP855 is derived from the murine
antibody L243 (22). The murine form (IgG2a) of the antibody was given to rhesus monkeys at a dose of 10 mg/kg
(bolus IV injection, single dose) and at 0.1 mg/kg (bolus IV
injections, daily for 10 days). Two animals received the high
dose of antibody. These two animals both developed acute
cardiopulmonary distress and died of severe pulmonary
edema within 20–25 min of the start of the infusion of the
antibody. The lower dose was well tolerated for the total
duration of the infusion period of 10 days. Thus, the side
effects were dose dependent. Most likely, the side effects
were also dependent on the Fc part of the antibody as Fab 2
fragments given at 0.6 to 6 mg/kg did not cause these side
effects (Table 1). Subsequently chimeric forms of the antibody were developed, which have a human Fc tail. The
IgG4 form of this antibody, CDP855, does not show significant binding to human, rhesus monkey or cynomolgus
Fc receptors, and thus is less likely to cause serious side
effects. The antibody was first tested in rhesus monkeys
at 1 mg/kg. This was well tolerated. Administration of this
antibody at 10 mg/kg antibody given over a 1-h period to
cynomolgus monkeys did not result in any clinical side
effects.
Graft survival and CMV infection
Untreated control animals rejected their graft within 7 days
(rejection days 4, 6, 6, 8) with signs of severe cellular rejection (23). Table 2 shows the animal survival and the cause
of death for all six CDP855-treated animals. Three animals
showed delayed graft rejection at 12–15 days post transplantation. Three animals had a short survival, but this was
not due to graft rejection as evidenced by the absence of
significant pathological changes in the grafts indicative for
rejection. All three animals had signs of viral infections,
which either directly or indirectly may have caused the
death of the animals. Two animals (455 and 141) had an
inflammatory process at the site of ureter–bladder anastomosis. This most likely caused a blockade of the ureter
and the animals passed very little urine the days just before
autopsy. In both the animals evidence for an active CMV
infection was found in the urinary bladder (typical CMV inclusions). Animal 141 also had severe peritonitis. This could
have been caused by urine leaking into the abdomen. Animal 583 had no signs of CMV infection on histopathology, but died of pneumonia, which was most likely of viral
origin: as there was no evidence of bacterial infection (no
gram positive staining, the pleural fluid was sterile upon culture) and in the lung syncytial cells were found. In a group
of 36 cynomolgus monkeys that received a kidney transplant under the same experimental conditions, and also
received more potent immunosuppression (sirolimus and
everolimus) (23) in the 2 years prior to this study, not one
early post-transplantation deaths occurred due to CMV disease or viral pneumonia. CMV antibodies were determined
in serum samples before transplantation and at autopsy. All
six animals had IgG antibodies before transplantation indicating that all recipients were latently infected with CMV.
No IgM antibody titers could be detected. The two animals that developed a proven CMV infection (455 and 141)
showed a slight decrease in CMV IgG antibodies, as well
Table 1: Side effects upon IV administration of L243 L243Fab2 and CDP855
Species
Fc isotype
Dose and frequency
N
Result
Rhesus monkey
Rhesus monkey
Rhesus monkey
Rhesus monkey
Rhesus monkey
Rhesus monkey
Murine IgG2a
Murine IgG2a
L243 Fab2
L243 Fab2
L243 Fab2 (none)
CDP855
Human IgG4
CDP855
Human IgG4
10 mg/kg, once
0.1 mg/kg/day, 10 days
0.6 mg/kg, once
2 mg/kg, once
6 mg/kg, once
1 mg/kg, once
2
1
1
1
2
2
Acute toxicity (shock), death after ±20 min
No significant side effects
No significant side effects
No significant side effects
No significant side effects
No significant side effects
10 mg/kg/day
3 days
6
No significant side effects
Cynomolgus monkey∗
∗ Animals
the same as in transplantation study.
Table 2: Outcome of kidney graft survival in cynomolgus monkeys treated with CDP855
Monkey
583∗
455
141
43∗
91
377
Day necropsy
6
7
8
12
13
15
Banff score
g
i
t
v
0
2
0
3
3
1
0
0
0
1
0–1
0
1
0–1
0–1
2
2
2
0
0
0
3
3
2
Histology kidney graft
Main diagnosis
No rejection
No rejection
No rejection
Grade IIA acute rejection
Grade IB acute rejection
Grade IA acute rejection
Pneumonia (viral)
Ureter obstruction due to CMV infection
Ureter obstruction due to CMV infection; peritonitis
Acute kidney graft rejection
Acute kidney graft rejection
Acute kidney graft rejection
g: glomerulitis; i: interstitial inflammation; t: tubulitis; v: intimal arteritis. 0 = no changes; 1, 2, 3: increasing Changes.
∗ These monkeys received prophylactic ganciclovir.
1758
American Journal of Transplantation 2004; 4: 1756–1761
Anti-Class-II Treatment in Kidney Transplantation
Table 3: CMV antibodies in transplanted monkeys
Monkey
Prophylactic ganciclovir
Day autopsy
Diagnosis
CMV IgM antibody∗
Day 0
Autopsy
CMV IgG antibody∗
Day 0
Autopsy
583
455
141
43
91
377
yes
6
7
8
12
13
15
Pneumonia (viral)
CMV infection
CMV infection
Acute kidney graft rejection
Acute kidney graft rejection
Acute kidney graft rejection
0.4
0.4
0.4
0.4
0.4
0.4
3.4
2
1.4
1.8
1.6
1.9
yes
0.4
0.5
0.4
0.4
0.4
0.5
4.8
1.5
0.7
3.2
1.1
2.5
∗ The figures represent a ratio of the OD of monkey serum divided by the OD of a negative human reference serum. Values above 1.1
are considered positive.
as animal 091, while the other animals showed a slight
increase in CMV IgG antibodies (Table 3).
dition of MHC-DR specific antibodies are known to block
the MLR presumably by preventing adequate recognition
by the T-cells (26–28). Whether this is limited to the direct
presentation pathway is unclear. It also seems likely that indirect presentation can be blocked as this is also mediated
by class-II molecules. Blocking this process in vivo by infusing the recipient with anti-DR antibodies may thus prevent
graft recognition and graft rejection. Early studies in rats
have shown that recipient-specific but not donor-specific
class-II antibodies delay graft survival, emphasizing that
the indirect pathway of antigen recognition is important
and can be blocked in allotransplantation (8). The results
from this study show that the anti-DR antibody CDP855 is
capable of blocking the alloresponse in vitro. The response
was never reduced completely to background levels, indicating that perhaps other class-II antigens (such as DQ)
play a minor role in antigen presentation as well.
Lymphocyte subset analysis showed that both T and B cells
were lower for the first 4 days post-transplantation. B-cells
(CD20 positive) remained depressed in all animals during
the whole post-transplantation period (Figure 2). The number of DR positive cells, comprising B-cells, monocytes and
possibly activated T cells, were low during the first week
post-transplantation, but these increased again during the
second week post-transplantation.
Discussion
Antigen presentation after organ transplantation occurs by
the direct presentation of donor MHC class-II molecules, as
well as by indirect presentation of donor MHC peptides in
recipient MHC class-II molecules to recipient T-cell receptors. The MLR is considered as an in vitro analogue of the
in vivo rejection process. The proliferation measured in this
assay depends a to a large extent on the direct presentation
of stimulator MHC class-II antigens, as unrelated class-II
identical individuals, differing for multiple minor antigens,
will show a significantly reduced proliferation in such MLR
assays, both in human (24) as well as in monkeys (25). Ad-
Kidney graft rejection in three CDP855-treated animals was
slightly but significantly delayed as compared to untreated
control animals. The antibody treatment resulted in B-cell
depletion from the circulation. This depletion could be the
result from B-cell kill, or it could be that the homing pattern of the B-cells had changed. Interestingly, CD20 negative and DR positive cells reappeared earlier than the
CD20 positive B-cells, indicating that these distinct cell
60
Mean CD20
Mean DR
% positive cells
50
40
30
20
10
Figure 2: Mean percentage of CD4,
CD20 and DR positive cells after
CDP855 treatment as determined
by immunofluorescence and FACS
analysis.
0
-10
-8
American Journal of Transplantation 2004; 4: 1756–1761
-6
-4
-2
0
2
4
6
8
10
12
14
16
18
20
Day post-transplantation
1759
Jonker et al.
populations responded differently to the treatment. These
results are in agreement with an earlier report when the
IgG1 isoform of the same antibody (gLE1) was used in
cynomolgus monkeys. gLE1 prolonged kidney allograft survival to 14–28 days and resulted in a similar short B-cell depletion (29). As the treatment was given only at the time
of transplantation, rejection was only delayed for a short
period and the grafts were lost due to cellular rejection at
2 weeks post-transplantation. The mechanism by which
the anti-MHC-class-II antibodies exert their effect remains
unclear. When inhibition of the direct presentation pathway
is the underlying mechanism, donor-specific anti-class-II
antibodies should be able to inhibit. However, in rats using
allele-specific anti-DR antibodies it has been demonstrated
that the effects are primarily exerted on recipient, as donorspecific antibodies did not have a significant effect (10).
Also in a xenotransplantation study, anti-DR treatment of
the recipient was effective (9). Our own previous data in
rhesus monkeys using other murine monoclonal antibodies showed some graft prolongation (30). The mechanism
by which the anti-DR treatment did block in vivo remains
unclear.
Three of the six animals treated with CDP855 developed a
viral infection shortly after transplantation. Two of these animals had a histologically proven CMV infection. In the third
animal, no typical CMV inclusion bodies were found. However, the clinical symptoms of this animal’s disease fit with
a CMV infection. A very high percentage of Macaques are
latently infected with CMV. As all animals in this study had
pre-existing anti-CMV antibodies, it is most likely that an activation of an endogenous latent CMV infection occurred.
In immunosuppressed macaques a latent CMV infection is
often activated and animals become productively infected
and may develop lesions and diseases related to CMV infection (31). In immunosuppressed animals with inflammatory lesions not related to CMV infection, CMV infection
appears to be attracted by the inflammatory process, replicates in the affected tissue and may aggravate the existing lesion (Kuhn, unpublished observations in SIV-infected
macaques). To our knowledge, it has not been described
earlier that anti-class-II antibodies can cause activation of
a viral infection. CMV can be activated in organ transplant
recipients due to the combination of an inflammatory response to the allograft combined with the immunosuppression. The allograft results in the activation of genes such
TNF-a and IFN-c , followed by up-regulation of transcription
factors AP-1 and NF-jB. These in turn are capable of activation of latent CMV (32,33). The immunosuppression could
then prevent an adequate attack of viremia. However, in
this study, CDP855 was only marginally immunosuppressive as graft survival was only marginally prolonged, and
it seems unlikely that the general immunosuppressive effect of CDP855 can be held responsible for the viral activation. In the same animal model using CsA, sirolimus
and everolimus (23) we did not observe CMV disease or
pneumonia in a large group of cynomolgus monkeys from
the same origin. Although we cannot exclude that a ureter
1760
obstruction was responsible for an inflammatory process
that subsequently triggered CMV disease in two animals,
this seems not very likely in view of our previous experience in this model. We, therefore, hypothesize that the
anti-DR antibody was more directly responsible for the reactivation of the virus. The antibody itself could not activate CMV in human CMV infected cells (Proesch and Volk,
personal communication). However, it has been described
that anti-DR and L243 in particular can trigger B cells to become activated and release TNF-alpha and activate NF-jB
(34,35). Monkeys treated with various dosages of the antibody but that did not receive a kidney allograft have not
developed CMV disease. Thus, both the transplantation
procedure and the antibody treatment may have acted in
concert resulting in CMV activation.
References
1. Thomas JM, Eckhoff DE, Contreras JL et al. Durable donorspecific T and B cell tolerance in rhesus macaques induced with
peritransplantation anti-CD3 immunotoxin and deoxyspergualin:
Absence of chronic allograft nephropathy. Transplantation 2000;
69: 2497–2503.
2. Knechtle SJ, Vargo D, Fechner J et al. FN18-CRM9 immunotoxin
promotes tolerance in primate renal allografts. Transplantation
1997; 63: 1–6.
3. Sachs DH. Mixed chimerism as an approach to transplantation
tolerance. Clin Immunol 2000; 95: S63–S68.
4. Kirk AD, Burkly LC, Batty DS et al. Treatment with humanized
monoclonal antibody against CD154 prevents acute renal allograft
rejection in nonhuman primates. Nat Med 1999; 5: 686–693.
5. Hart DN, Fabre JW. Passive enhancement of rat renal allografts
using mouse monoclonal xenoantibodies. Transplantation 1981;
32: 431–436.
6. Kruisbeek AM, Bridges S, Carmen J, Longo DL, Mond JJ. In vivo
treatment of neonatal mice with anti-I-A antibodies interferes with
the development of the class I, class II, and Mls-reactive proliferating T cell subset. J Immunol 1985; 134: 3597–3604.
7. McDevitt HO, Perry R, Steinman LA. Monoclonal anti-Ia antibody
therapy in animal models of autoimmune disease. Ciba Found
Symp 1987; 129: 184–193.
8. Priestley CA, Spencer SC, Sawyer GJ, Fabre JW. Suppression of
kidney allograft rejection across full MHC barriers by recipientspecific antibodies to class II MHC antigens. Transplantation
1992; 53: 1024–1032.
9. Saxton NE, Hallaway RV, Ladyman HM et al. Anti-major histocompatibility complex class II treatment prevents graft rejection
in the hamster-to-rat cardiac xenograft. Transplantation 1999; 67:
1599–1606.
10. Smith RM, Chen ZK, Foulkes R, Metcalfe SM, Wraith DC. Prolongation of murine vascularized heart allograft survival by recipientspecific anti-major histocompatibility complex class II antibody.
Transplantation 1997; 64: 525–528.
11. Foulkes R. Preclinical safety evaluation of monoclonal antibodies.
Toxicology 2002; 174: 21–26.
12. Chatterjee SN, Billings R, Bernoco D, Terasaki P. Early evaluation
of Ia monoclonal antibodies in prolonging non-human primate skin
allograft survival. Proc Eur Dial Transplant Assoc 1981; 18: 362–
366.
13. Chatterjee S, Bernoco D, Billing R. Treatment with anti-Ia
and antiblast/monocyte monoclonal antibodies can prolong skin
American Journal of Transplantation 2004; 4: 1756–1761
Anti-Class-II Treatment in Kidney Transplantation
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
allograft survival in nonhuman primates. Hybridoma 1982; 1: 369–
377.
Jonker M, Nooij FJ, den Butter G, van Lambalgen R, Fuccello AJ.
Side effects and immunogenicity of murine lymphocyte-specific
monoclonal antibodies in subhuman primates. Transplantation
1988; 45: 677–682.
Jonker M, van Lambalgen R, Mitchell DJ, Durham SK, Steinman
L. Successful treatment of EAE in rhesus monkeys with MHC
class II specific monoclonal antibodies. J Autoimmun 1988; 1:
399–414.
Bontrop RE, Otting N, Slierendregt BL, Lanchbury JS. Evolution
of major histocompatibility complex polymorphisms and T-cell receptor diversity in primates. Immunol Rev 1995; 143: 33–62.
Doxiadis GG, Otting N, Antunes SG et al. Characterization of the
ABO blood group genes in macaques: Evidence for convergent
evolution. Tissue Antigens 1998; 51: 321–326.
Barclay NA, Birkeland ML, Brown MH et al. The Leucocyte Antigen Facts Book. Academic Press:New York, 1993.
Neuhaus P, Neuhaus R, Wiersema HD, Borleffs JC, Balner H.
The technique of kidney transplantation in rhesus monkeys. J
Med Primatol 1982; 11: 155–162.
Ossevoort MA, Ringers J, Kuhn EM et al. Prevention of renal
allograft rejection in primates by blocking the B7/CD28 pathway.
Transplantation 1999; 68: 1010–1018.
Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55: 713–723.
Morgan A, Jones ND, Nesbitt AM, Chaplin L, Bodmer MW,
Emtage JS. The N-terminal end of the CH2 domain of chimeric
human IgG1 anti-HLA-DR is necessary for C1q, Fc gamma RI and
Fc gamma RIII binding. Immunology 1995; 86: 319–324.
Schuurman HJ, Ringers J, Schuler W, Slingerland W, Jonker M.
Oral efficacy of the macrolide immunosuppressant SDZ RAD and
of cyclosporine microemulsion in cynomolgus monkey kidney allotransplantation. Transplantation 2000; 69: 737–742.
van Rood JJ, van Leeuwen A, Termijtelen A, Keuning JJ. B-cell
antibodies, Ia-like determinants, and their relation to MLC determinants in man. Transplant Rev 1976; 30: 122–139.
American Journal of Transplantation 2004; 4: 1756–1761
25. Jonker M, van Meurs G, Balner H. Typing for RhLA-D in rhesus
monkeys: I. Characteristics of ten groups of homozygous typing
cells. Tissue Antigens 1982; 19: 60–68.
26. Steel CM, Van Heyningen V, Guy K, Cohen BB, Deane DL. Influence of monoclonal anti-Ia like antibodies on activation of human
lymphocytes. Immunology 1982; 47: 597–603.
27. Effros RB, Hulette CM, Ettenger R et al. A human-human hybridoma secreting anti-HLA class II antibody. J Immunol 1986;
137: 1599–603.
28. Kalil J, Wollman EE. Role of class I and class II antigens in the allogenic stimulation: Class I and class II recognition in allogenic stimulation; blocking of MLR by monoclonal antibodies and F(ab )2
fragments. Cell Immunol 1983; 79: 367–373.
29. Shapiro ME, Liu M, Smith R, Saxton NE, Nesbitt AM, Foulkes R.
Anti-MHC class II Mabs suppress allogeneic responses in solid
organ transplantation in mice and primates. Transplantation 1998;
65: 377.
30. Jonker M. The importance of non-human primates for preclinical testing of immunosuppressive monoclonal antibodies. Semin
Immunol 1990; 2: 427–436.
31. Kuhn EM, Stolte N, Matz-Rensing K et al. Immunohistochemical
studies of productive rhesus cytomegalovirus infection in rhesus monkeys (Macaca mulatta) infected with simian immunodeficiency virus. Vet Pathol 1999; 36: 51–56.
32. Hummel M, Abecassis MM. A model for reactivation of
CMV from latency. J Clin Virol 2002; 25(Suppl 2): S123–
S136.
33. Bumgardner GL, Orosz CG. Transplantation and cytokines. Semin
Liver Dis 1999; 19: 189–204.
34. Coral S, Pucillo C, Leonardi A, Fonsatti E, Altomonte M, Maio
M. Triggering of HLA-DR antigens differentially modulates tumor
necrosis factor alpha release by B cells at distinct stage of maturation. Cell Growth Differ 1997; 8: 581–588.
35. Leonardi A, Altomonte M, Maio M et al. Biphasic control
of NF-kappa B activation induced by the triggering of HLADR antigens expressed on B cells. Cytokine 1997; 9: 295–
299.
1761