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*
Department of Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden;
Department of Immunology, Stockholm University, Stockholm, Sweden; and
Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RII/CD23), suggesting that the effect on in vivo Ab responses is
caused by increased Ag presentation. We here show that mice carrying
the MHC class II Ab molecule (e.g., C57BL/6 and 129/Sv) do
not produce Abs to BSA when immunized with BSA-2,4,6-trinitrophenyl
(TNP) in complex with monoclonal IgE anti-TNP. In contrast, strains
of all other MHC haplotypes tested (H-2d, H-2k,
H-2p, H-2q, and H-2s) respond
vigorously to IgE/BSA-TNP complexes, with Ab responses several
hundred-fold higher than the responses in H-2b mice.
C57BL/6 mice were unable to produce a carrier-specific response also
after immunization with IgE/OVA-TNP, IgE/diphtheria toxoid-TNP, or
IgE/tetanus toxoid-TNP. Although the low responsiveness mapped to the
Ab region, responsiveness was not restored in C57BL/6 mice
carrying transgenic Ak, suggesting that a nonclassical
A-region-encoded gene product is involved. Most importantly, our data
call attention to the fact that the C57BL/6 and 129 mouse strains,
which are widely used for producing transgenic animals, have defective
immune responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most recently described immunoregulatory Ig is IgE. When 10 to 100
µg monoclonal IgE
anti-TNP4 was
administered to mice together with 20 to 200 µg BSA-TNP, the
BSA-specific IgG response was dramatically enhanced as compared with
that in mice given BSA-TNP alone (3, 4). Not only the primary IgG
response, but also the production of BSA-specific IgE and IgM as well
as the memory response, was enhanced by IgE (4). IgE enhanced the
response also to two other TNP-conjugated proteins (OVA and TT) but did
not induce Ab responses in T cell-deficient nude mice, showing that the
need for T cell help could not be circumvented (4). The immunizations
were performed without adjuvants in physiologic salt solutions. IgE/Ag
complexes gave rise to a very rapid, secondary type of reaction with a
peak in the IgG response 6 days after priming (5). The capacity of IgE
to enhance the in vivo immune response was completely abolished when
mice were pretreated with mAbs specific for the low affinity receptor
for IgE (FcRII/CD23) (3, 4) and in mice deficient of CD23 (6). Ag
covalently bound to CD23-specific mAbs also induced a strong response,
presumably by targeting Ag to CD23 (7). CD23 has been shown both in
human (8, 9, 10) and murine (11) in vitro systems to increase the capacity
of B cells to present Ag to T cells, presumably via endocytosis of the
IgE/Ag complexes (12). Whether this mechanism explains
IgE/CD23-mediated enhancement of in vivo Ab responses is not known but
remains an attractive possibility. It has been hypothesized that IgE
via CD23 can enhance the response to allergens and thus be partly
responsible for perpetuation of allergic diseases (13). Immunization
with IgE/Ag was recently demonstrated to induce a Th2 type of response
in vitro (14). Apart from its role in an immunostimulatory circuit,
CD23 has been implied as a negative regulator of B cell activation (15)
and as a multifunctional cytokine (16).
In the course of our studies of IgE-mediated immunoregulation, we found that TNP-specific IgE was unable to enhance the Ab responses to four unrelated protein Ags (BSA-TNP, OVA-TNP, DT-TNP, and TT-TNP) in B6 mice, whereas the same response in (B6 x DBA/2)F1 mice was strongly enhanced. We were intrigued by the very clear-cut and, to us, unexpected low response in one of the most commonly used inbred mouse strains. The fact that practically all knockout mice are produced from embryonic stem cells originating from the mouse strain 129 transferred to blastocysts from B6 mice, both of which carry the MHC haplotype H-2b, made the finding worth further studies. Although earlier reports have indicated various low responder phenomena in the B6 mouse strain (reviewed in 17 , this knowledge is not widespread, and, as far as we are aware, the phenomenon has not been considered in reports about the immune response in knockout mice. We here show that the low responsiveness to BSA in complex with IgE is linked to the MHC class II Ab region and present data indicating that A-region-encoded products other than the classical A molecules may be involved.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c, C57BL/6 (B6), CBA/J, DBA/2, SJL/J, and 129/SV were
purchased from Bommice (Ry, Denmark). BALB.B and B10.D2 were bred in
the animal facilities at the Karolinska Institute, Stockholm. C57BL/10
(B10), B10.A, B10.A(4R), B10.A(5R), and B10.MBR were purchased from The
Jackson Laboratories (Bar Harbor, ME). DBA/1, SWR, B10.P, and B10.Q
were bred in the animal facilities at the Biomedical Center, Uppsala
University, and (B6 x CBA/J)F1, (B6 x
DBA/2)F1, (BALB/c x 129/Sv)F1, and
(B6 x 129/Sv)F1 at the Department of Genetics and
Pathology, Uppsala University. Groups of 3 to 8 male or female mice, 6
to 24 wk of age, were used and matched for age and sex within each
experiment. The ability to respond to TNP-specific IgE and BSA-TNP is
unaffected by sex and age (5). H-2Ak transgenic mice on a
B6 background were obtained by intercross of the transgenic lines
A
46 (Ak) and Aß42 (Aßk) (18). The
genotype of the offspring was analyzed in Southern blots as described
(18, 19), and double-transgenic ((A46 x Aß42)Tg) mice as
well as double-negative (B6(Tg-/-)) littermates were used
in the experiments.
Antibodies
The hybridoma cell line IGELb4 (mouse IgE/
-anti-TNP) (20)
was grown in DMEM with 5% FCS. IGELb4 was purified from the culture
supernatant by affinity chromatography on a Sepharose column coupled
with monoclonal rat-anti-mouse , 187.1.10 (21). Bound Ab was
eluted with 0.1 M glycine-HCl buffer, pH 2.8. Protein concentrations
were determined by absorbance at 280 nm, assuming that an OD of 1.5
equals 1 mg/ml of mAb.
Antigens
BSA and OVA were obtained from Sigma (St. Louis, MO), and DT and TT from The National Bacteriologic Laboratory (Stockholm, Sweden). TNP (Sigma) was conjugated to BSA, OVA, DT, or TT in 0.28 M caccodylate buffer, pH 6.9 (22). After different incubation times at room temperature the reaction was stopped by an excess of glycyl-glycine, 1 mg/ml (Merck, Darmstadt, Germany). The proteins were dialysed against PBS, and the number of incorporated TNP residues was determined (22). Subscripts indicate number of TNP per protein molecule; BSA-TNP23, OVA-TNP1, DT-TNP18, and TT-TNP10 were used. The branched peptide MAP1 comprises four copies of the sequence (VTEEI)3 derived from the malaria Ag Pf332 and was synthesized as previously described (23). Ags were stored at 4°C as sterile solutions.
Immunizations
Mice were immunized with indicated amounts of Abs in 0.1 ml PBS in the tail vein, followed within 1 h by Ag in 0.1 ml PBS, or s.c. in the flanks with 50 µl BSA-TNP emulsified 1:1 in CFA, or s.c. in both hind foot pads with 25 µg MAP1 emulsified 1:1 in CFA.
ELISA
Mice were bled from the tail veins, and the sera were analyzed
by ELISA as described (4). As standards (see Table II
and Figs. 1 and 3), hyperimmune antisera against BSA, OVA, DT, and TT were used. A
value of 10,000 U/ml (corresponding to 4,500 ng/ml BSA-specific IgG)
was assigned to the highest concentration used. In later experiments
(see Table I and Figs. 2 and 4), the BSA-specific standard serum was
affinity purified on BSA-Sepharose, and the concentration of
BSA-specific IgG was determined in µg/ml. The MAP1-specific ELISA has
been described (23). Standard curves and calculations were done by the
use of a Softmax program (Molecular Devices Corporation, Menlo Park,
CA). Statistical differences were determined by Student’s t
test, and stimulation indices (SI) were calculated by dividing the
geometrical mean (anti-log of log10 values) of the
experimental group with the geometrical mean of the control group.
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Double-color immunofluorescence staining of spleen cells was performed. Briefly, 106 cells were suspended in PBS containing 2% FCS and 0.01% sodium azide and incubated for 30 min at 4°C with FITC-conjugated anti-Ak mAb (clone 11.5.2; PharMingen, San Diego, CA). Cells were washed and incubated for another 30 min at 4°C with phycoerythrin (PE)-conjugated anti-CD23 mAb (clone B3B4; PharMingen). After incubation, cells were washed, and data from 10,000 cells were collected and analyzed using a FACScan (Becton Dickinson, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNP-specific IgE Abs enhance the BSA-specific IgM, IgG, and IgE
response in vivo when given together with BSA-TNP (3, 4). However,
during our studies of this phenomenon we found that IgE could not
induce enhancement of the BSA-response in the B6 strain of mice. To
investigate this further, the ability of TNP-specific IgE Abs to induce
an enhanced response to various TNP-conjugated carriers was
investigated. B6 and (B6 x DBA/2)F1 animals were
immunized with 50 µg monoclonal TNP-specific IgE (IGELb4) and 20 µg
BSA-TNP, OVA-TNP, DT-TNP or TT-TNP. Controls received Ag alone. Seven,
14 and 21 days later the mice were bled, and the sera were analyzed for
carrier-specific IgG in ELISA. As seen in Figure 1
, the Ab response to the different
TNP-conjugated carriers was enhanced by IgE in (B6 x
DBA/2)F1 but not in B6 mice. In previous studies, 20 µg
of BSA-TNP was the optimal dose for enhancement (4). To test whether
the low responsiveness to BSA could be overcome by using higher amounts
of BSA-TNP, an Ag-titration was again performed (Table I). BSA-TNP/IgE (200 µg) induced a weak
enhancement (5.2-fold; p < 0.005) in B6 mice that,
however, should be compared with the 50-fold enhancement to the same
dose in (B6 x DBA/2)F1 hybrids. Lower doses of Ag did
not induce any significant enhancement in B6 mice although the SI in
(B6 x DBA/2) animals was 1699 (20 µg) and 2690 (2 µg).
IgE-mediated enhancement of Ab responses is strictly Ag specific (3, 4). When TNP-specific IgE is administered with BSA-TNP and a control Ag
(not recognized by the IgE), only the BSA-specific response is
enhanced. When TNP-specific IgE is administered with unconjugated BSA,
the BSA-specific response is not enhanced. The specificity of the
IgE-mediated enhancement is confirmed in Table I, which shows that the
OVA-specific response is not modulated. The specificity of the
IgE-mediated enhancement was regularly confirmed during the other
experiments in the present study (not shown).
B6 mice respond to BSA-TNP administered in CFA
It has been reported that H-2b mice respond to BSA
when the Ag is administered in CFA (18). To investigate if B6 mice also
responded to BSA-TNP, B6 and (B6 x DBA/2)F1 mice were
immunized with 2, 20, or 200 µg BSA-TNP in CFA. The BSA-specific IgG
response was measured in sera collected 7, 14, and 21 days
postimmunization (Fig. 2). B6 mice were
indeed capable of mounting a high anti-BSA response when high doses
of Ag were administered in CFA. However, the overall magnitude of the
response was lower than in (B6 x DBA/2)F1 mice. This
experiment was performed three times. In the two experiments not shown,
B6 mice responded also to 20 µg BSA-TNP in CFA, indicating that this
dose is on the borderline of what is required for stimulation. Thus, B6
mice can produce high amounts of BSA-specific IgG when a potent
adjuvant is used.
Linkage of the low responder phenotype to the H-2Ab region
Next, a panel of different mouse strains were immunized with 50
µg monoclonal TNP-specific IgE (IGELb4) and 20 µg BSA-TNP or
BSA-TNP alone. Coadministration of IgE Abs and hapten-carrier induces a
rapid IgG production that reaches a plateau level as early as 7 days
after injection (Refs. 3–5 and Fig. 1). The Ab production in the
different strains of mice was therefore measured at this early
timepoint. Representative experiments (of at least two performed with
each strain) are shown in Table II. Mice
with the H-2b haplotype were low responders, whereas mice
with all other haplotypes tested (H-2d, H-2k,
H-2p, H-2q, and H-2s) were
responders. The SI in responders varied from 44 to 190, and the
differences were highly significant. In the three H-2b
mouse strains tested, the SI ranged from 0.4 to 2.1. For unknown
reasons, the control response in 129/Sv was higher than in other
strains. Nevertheless, IgE did not induce enhancement. B6 mice express
only one class II molecule, A but not E (24). However, lack of E cannot
solely explain the low responsiveness since two of the responder
strains, DBA/1 and SJL, also lack expression of the E molecule (24).
Hybrids between a responder and a low responder strain were responders,
whereas hybrids between two low responders remained low responders,
pointing to dominance of the responder phenotype.
To determine whether the correlation of the low responder phenotype to
H-2b was fortuitous or reflected a true linkage, mice
congenic for the H-2 locus were immunized with BSA-TNP with or without
IgE (Fig. 3A). The H-2 locus
clearly determined the outcome of IgE-mediated enhancement: Mice with
H-2b on a BALB/c background (BALB.B) were low responders
whereas mice with H-2d on a B10 background (B10.D2) were
responders. Further genetic mapping of the low responder phenotype was
performed by using intra-MHC recombinant strains where a crossing over
has taken place within the H-2 complex. From Figure 3B, it
is evident that b alleles to the left (centromeric) of the crossing
over point in the E gene (B10.A(5R)) rendered the mice low
responsive to IgE-mediated enhancement, whereas b alleles to the right
(telomeric) of this crossing over point (B10.A(4R)) were compatible
with IgE-mediated enhancement, resulting in a 33- to 108-fold
enhancement of the response. The B10.MBR mice, which have a
recombination between the locus for K and Aß (25) rendering them
H-2KbAkEkDq, were
responsive to IgE-mediated enhancement with a SI of 26. The experiments
in Figure 3 were performed twice. We conclude that low responsiveness
is linked to the MHC class II Ab region.
H-2b mice with transgenic H-2Ak are low responders to BSA-TNP administered together with specific IgE
The H-2A region, as defined by intra-MHC recombinant mouse
strains, is approximately 170 kb large and encompasses genes other than
those encoding A and Aß (reviewed in 26 . We wanted to
determine whether the H-2A-linked low responsiveness to BSA was due to
the A molecules themselves or to other gene products encoded in this
region. To this end, we used B6 mice expressing transgenic
Ak at the same levels as analogous "natural" mice (18).
The transgenes encode only the A or Aß genes, and nothing else
from the 170-kb A-region. (B6 x CBA)F1 mice respond
very well to immunization with TNP-specific IgE and BSA-TNP (Table II).
We reasoned that a positive response in Ak-transgenic mice,
which express both Ak and Ab (18) and therefore
with regard to H-2A should be similar to (B6 x CBA)F1
hybrids, would confirm that H-2A was the molecule of interest.
Inability of transgenic Ak to confer responsiveness would
indicate the requirement for other, closely linked effector molecules
of the H-2b type that were not encoded by the transgenes.
Offspring from the intercross breeding between the transgenic lines
A46 (Ak) and Aß42 (Aßk) (18) were
tested in Southern blots. As expected, the breeding resulted in
approximately 25% double-transgenic mice ((A46 x Aß42)Tg),
expressing complete Tg Ak molecules in addition to the
Ab derived from the B6 background strain, and 25%
double-negative mice (B6(Tg-/-)), expressing only
Ab. These two strains and (B6 x CBA)F1
mice were immunized with 50 µg TNP-specific IgE together with 100
µg BSA-TNP, and the sera were tested in ELISA. The BSA-specific IgG
levels in double-transgenic mice were indistinguishable from the levels
in unimmunized animals and in mice receiving Ag alone, whereas the
response of (B6 x CBA)F1 mice was augmented more than
100-fold (Fig. 4). This experiment was
repeated twice and in addition performed three times with the
"standard" dose of BSA-TNP (20 µg). In only one of these
experiments could we detect a weak, but significant, enhancement of the
BSA-specific response in Ak double-transgenic mice
(5.4-fold, p < 0.01) (not shown), similar in magnitude
to the 5.2-fold enhancement that was observed in normal B6 mice given
200 µg Ag (Table I). The 5.4-fold enhancement in double-transgenic
animals should be compared with the 172-fold enhancement in (B6 x
CBA)F1 mice in the same experiment (not shown). In
conclusion, transgenic responder A molecules did not confer
responsiveness to B6 mice.
Expression and function of transgenic Ak
To confirm that the double-transgenic mice expressed
Ak on their CD23+ spleen cells (which are the
effector cells in IgE-mediated enhancement (3, 4, 6)), the expression
of Ak and CD23 on splenocytes from double-transgenic,
double-negative, and (B6 x CBA)F1 mice was analyzed
by flow cytometry. A representative example of each mouse type is shown
in Figure 5. As expected (18), spleen
cells from double-transgenic and (B6 x CBA)F1 mice
expressed similar levels of Ak, whereas cells from
double-negative littermates were negative (Fig. 5A).
CD23+Ak+ splenocytes (which are primarily B
cells (27, 28)) constituted 10% of the cells in double-transgenic
mice, 24.2% in (B6 x CBA)F1 mice, and 1.7% in
double-negative mice (Fig. 5, B–D). It is known that
extreme overexpression of transgenic Aß-chains are toxic to B cells
(29). Since the transgenic line used in our experiments does not
overexpress Aß (18), the reason for the lower B cell numbers is not
known.
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Thus, transgenic Ak molecules were able to reconstitute the
ability of B6 mice to respond to MAP1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We here describe a previously unknown type of low responsiveness apparently restricted to H-2Ab mice. B6 mice produce no, or very low, titers of carrier-specific Abs after immunization with BSA-TNP, OVA-TNP, DT-TNP, and TT-TNP administered with TNP-specific IgE mAbs whereas (B6 x DBA/2)F1 hybrids in the same system produce very high titers. Further studies of the response to one of these proteins, BSA, revealed that strains of all MHC haplotypes other than H-2b (i.e., H-2d, H-2k, H-2p, H-2q, and H-2s) respond vigorously to IgE/BSA-TNP and that the low responder phenotype mapped to the H-2Ab region. We did not genetically map the low responsiveness to IgE/OVA-TNP, IgE/DT-TNP, or IgE/TT-TNP in B6 mice, but it is likely that it is also Ab restricted. Immunization of B6 mice with BSA-TNP in CFA induced a strong BSA response. This indicates that studying the immune response after immunization with potent adjuvants may hide the "fine tuning" of the immune response, such as certain nonresponder situations that will be revealed only when more physiologic immunization regimes are used.
MHC-linked nonresponder phenomena are primarily described for simple
Ags such as synthetic polyamino acids (35) whereas Ags in the form of
complex molecules, containing many different epitopes, usually generate
responses with all types of MHC. What then is the explanation for the
general low responsiveness of B6 mice in our system? Its linkage to the
class II H-2A region suggested a defect in presentation of antigenic
peptides to T helper cells. However, it seemed unlikely that none of
the peptides generated by cleavage of the relatively large protein Ags
tested would fit into the binding groove of the Ab
molecule. The finding that B6 mice are in fact able to produce
BSA-specific Abs when challenged with high doses of BSA-TNP/IgE or with
the Ag in CFA shows that Ag presentation can take place and that
BSA-specific B cells as well as T helper cells are present. Thus, the
low responder phenotype is relative rather than absolute, arguing
against the hypothesis that Ab is unable per se to bind
BSA-peptides. It seems more feasible that a defect in processing or
intracellular transport of antigenic peptides is involved. The idea
that molecules other than H-2A could be important received experimental
support when B6 mice, expressing transgenic class II molecules
(Ak) from a responder haplotype, in addition to their own
Ab, remained low responders to IgE/BSA-TNP while (B6
x CBA)F1 control mice, also expressing a mixture of
Ab and Ak, responded efficiently (Fig. 4). As
detailed in Results, we have failed to find likely trivial
explanations for the inability of transgenic Ak to restore
responsiveness in B6 mice. The level of transgenic Ak per B
cell was similar to the level of endogenous Ak in (B6
x CBA)F1 mice. Although the number of
CD23+Ak+ spleen cells in double-transgenic mice
was only 41% of that in (B6 x CBA)F1 mice (Fig. 5),
we find it highly unlikely that this relatively small reduction in B
cell numbers in the transgenic mice would explain their complete
nonresponsiveness and the enormous difference in responsiveness between
double-transgenic and (B6 x CBA)F1 mice. Moreover,
transgenic Ak completely restored the ability of B6 mice to
produce Abs against a synthetic peptide to which B6 mice are
nonresponders, thus demonstrating that the Ak molecules are
indeed functional in the transgenic animals (Table III). Therefore, we
find that the most likely explanation for the inability to reverse the
low responsiveness in B6 mice with transgenic Ak is that a
nonclassical A-region-encoded factor is required for efficient
processing and presentation of Ag in complex with IgE (and possibly
also for other types of immunizations) and that the b-haplotype of this
factor is functioning poorly. Known A-region-encoded nonclassical gene
products of importance for class II-mediated Ag presentation are H2-M
(36) and H2-O (37). H2-M is required for efficient removal of the class
II-associated invariant chain peptide (CLIP) fragment of the Ii from
class II, a step necessary for the ability of class II to bind
exogenous peptides (38, 39). Accordingly, H2-M deficient mice express
class II molecules loaded with CLIP instead of with the normal wide
spectrum of peptides (40, 41, 42). The human counterpart to H2-O (HLA-DO)
is a lysosomal resident in B cells and forms stable complexes with
HLA-DM, the human equivalent to H2-M (43). Both H2-M and H2-O are
oligomorphic, with sequence variations of at the most four amino acids
(44). It cannot be excluded that these variations may play a role in
the complicated interactions between Ii, H2-M, and H2-O necessary for
efficient Ag presentation. Unlike AkAßk
and AdAßd, Ab and
Aßb are extremely dependent on Ii for assembly into
stable AbAßb heterodimers (45). This
raises the question of whether Ab molecules are targeted
differently inside the cell than, e.g., Ak and
Ad and therefore do not end up in the same endocytic
compartments as IgE/Ag complexes. Analysis of the role of H2-M for MHC
class II function in vivo in gene-targeted mice has been concentrated
on the structure of the MHC/peptide complex and the T cell repertoire,
and, to our knowledge, there is no report on how this could affect Ab
responses. Nevertheless, the interpretation of such data with regard to
possibly malfunctioning H2-Mb would be complicated by the
fact that the H2-M deficient mice described are all of the
H-2b haplotype (40, 41, 42). Finally, although H2-M and/or H2-O
seem to be the most likely candidates for the observed nonclassical
A-region-encoded influence on Ab production, unidentified genes in this
region may exist and be responsible for observed results.
Regardless of the mechanism behind the H-2b-linked low responsiveness, the fact that one of the most commonly used laboratory mouse strains has an abnormal way of responding to foreign proteins is an intriguing finding. Since virtually all knockout and transgenic mouse strains are generated in B6/129 chimeras, this has implications for the coming era of studies of immune responses in such animals. The use of alternative embryonic stem cells, such as the recently described cell line derived from the H-2q strain DBA/1 (46), may give rise to mouse strains that are more representative for normal immune responses.
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Acknowledgments |
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Footnotes |
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2 Present address: Dr. Susanna Chomez, Laboratoire de Physiologie Animale, Universitè Libre de Bruxelles, 67 rue des Chevaux, B-1640 Rhode-St-Genèse, Belgium. E-mail address:
3 Address correspondence and reprint requests to Dr. Birgitta Heyman, Unit of Pathology, Department of Genetics and Pathology, Uppsala University Hospital, S-751 85 Uppsala, Sweden. E-mail address:
4 Abbreviations used in this paper: TNP, 2,4,6-trinitrophenyl; B6, C57BL/6; DT, diphtheria toxoid; Ii, invariant chain; MAP, multiple antigen peptide; TT, tetanus toxoid; SI, stimulation index.
Received for publication March 2, 1998. Accepted for publication April 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RII by antigen-anti-FcRII conjugates. J. Immunol. 152:4388.[Abstract]
receptor II) from the surface of B lymphocytes generates a 16-kDa intracellular fragment. Eur. J. Immunol. 22:1573.[Medline]
k/Aßk transgenic mice. J. Immunol. 144:2865.[Abstract]
chain specific mAb, 187.1.10, purification, immunochemical properties and its utility as general secondary antibody reagent. J. Immunol. Methods 74:93.[Medline]
and E ß Ia polypeptide chains in mice of different H-2 haplotypes. Immunogenetics 12:321.[Medline]
RII). J. Immunol. 148:2340.[Abstract]
ß dimers and facilitates peptide loading. Cell 82:155.[Medline]
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