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1 From the Laboratory of Immunology, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; and the 2 Department of Ophthalmology, Jichi Medical School, Tochigi, Japan.
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Abstract |
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METHODS. Fully mismatched orthotopic corneal transplantation was performed in BALB/c hosts that had their CLNs excised before transplantation (CLN-). Normal hosts (CLN+), splenectomized mice (Sp-), and those without either CLNs or spleen (CLN-/Sp-) served as comparison groups. To determine the contribution of CLNs to alloimmunity more directly, CLN- mice were reconstituted by grafting LNs from other BALB/c mice to their cervical lymphatic chains, thus deriving CLN-/+ mice. Tetramethyl rhodamine isothiocyanate’s (TRITC) flow to draining CLNs was used as a measure of afferent lymph flow. Graft survival and allospecific delayed-type hypersensitivity (DTH) were used as measures of alloreactivity.
RESULTS. Fifty percent of normal control and 12% of Sp- hosts accepted the allografts. In contrast, 100% of CLN- and 88% of CLN-/Sp- hosts accepted allografts indefinitely (P < 0.01). Additionally, all CLN- hosts failed to demonstrate allospecific DTH (P < 0.001). CLN-/+ mice reconstituted with LN from naïve animals showed graft survival rates and DTH responses that were indistinguishable from those of naïve CLN+ mice. Of particular interest, however, is that mice reconstituted with CLNs from hosts with rejected corneal grafts had swift rejection of subsequent corneal grafts and exhibited strong donor-specific DTH. In contrast, mice reconstituted with CLNs from hosts with accepted corneal grafts showed rejection of subsequent corneal grafts in a manner that was indistinguishable from rejection in naïve CLN+ hosts.
CONCLUSIONS. Draining CLNs play a critical role in allosensitization and rejection. In contrast to the spleen, draining CLNs do not appear to play a critical role in tolerance induction in corneal transplantation.
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Introduction |
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Cervical lymph nodes (CLNs) drain the head and facial region, including the eyes,4 5 and have been implicated in both mucosal antigen-specific immunization and tolerance.5 6 7 8 In a classic series of experiments Wolvers et al.7 showed that the induction of immunologic tolerance to intranasal antigens is fully dependent on the presence of the native cervical LNs and that this tolerance induction cannot be replaced by peripheral (noncervical) LNs transplanted to the same site. Although it is known that CLNs also receive afferent lymphatics from the ocular compartment5 and that alloreactive cytotoxic T cells are generated in draining CLNs after high-risk corneal transplantation,9 the functional role of CLNs in the graft rejection process has not been directly studied. Moreover, because a number of secondary lymphoid organs, including the spleen, are involved in generation of allospecific responses,10 11 the direct contribution of CLNs to corneal alloimmunity remains to be determined. Finally, it has remained unclear whether the alloimmune response generated to corneal grafts in CLNs is primarily sensitizing or tolerance-inducing—that is, whether the overall in vivo effect of the donor-specific response generated in CLNs after transplantation promotes graft rejection or acceptance.
In the present study we investigated the role of CLNs in corneal alloimmunity, first by excising them from transplant-recipient mice (CLN-) and comparing graft survival and generation of donor (allo)-specific delayed-type hypersensitivity (DTH) to intact hosts endowed with their native CLNs (CLN+). In addition, CLN- mice were reconstituted by grafting LNs from other syngeneic naïve animals or from syngeneic mice that had previously been corneally graft recipients, to determine whether the functional role of the CLNs could be reestablished and whether allospecific (graft-destructive or tolerance-inducing) immunity could be adoptively transferred. In the aggregate, our data strongly suggest that CLNs, in contrast to the spleen, which plays a principal role in tolerance induction, play a critical and necessary role in allosensitization and corneal graft rejection.
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Methods |
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Orthotopic Corneal Transplantation and Definition of Graft
Rejection
Orthotopic penetrating keratoplasty was performed as described
previously in one (right) eye of each mouse.12
Briefly,
after induction of mydriasis, the recipient host bed was marked with a
trephine and excised with microscissors to a size of 1.5 mm. The donor
cornea was excised with a 2.0-mm trephine (Storz, St. Louis, MO) and
transplanted into the host corneal bed with interrupted 11-0 nylon
sutures (Sharpoint, Vanguard, TX). The corneal sutures were
removed 7 days after surgery. Eyes with the complication of
postoperative cataract, infection, or anterior synechiae formation were
excluded from the study. The corneal grafts were observed weekly by
slit lamp biomicroscopy. Grafts were defined as rejected when they
became opaque and the iris details could not be recognized clearly
using a standardized opacity-grading scheme. Kaplan–Meier analysis was
adopted to construct survival curves, and the log-rank test was used to
compare the probability of corneal graft survival in different
settings. P < 0.05 was considered significant.
Surgical Removal of CLNs and Spleen
After induction of deep anesthesia, a small incision was made in
the neck skin under the operating microscope, and the superficial
cervical and facial LNs (usually two to three each) were removed
bilaterally for generation of LN-deficient CLN-
mice. The incision was then closed with several 8-0 nylon sutures.
Splenectomy was performed similarly, and the skin wound closed with 8-0
nylon sutures. Concurrent removal of both spleen and CLNs
(CLN-/Sp-) or splenectomy
alone (Sp-) was performed in some (n
= 8, each group) mice. In separate experiments not involving
transplantation, CLN- mice were examined at
various time points (2 to 8 weeks after LN excision) to ensure that the
technique had led to indefinite loss of lymphatic flow to the cervical
area. For the experiments described herein, unless otherwise noted,
CLN- mice were used for corneal transplantation
at least 4 weeks after LN excision.
Assay for DTH
To evaluate the allospecific cell-mediated immune response in
CLN- mice, DTH responses were determined by an
ear-swelling assay. Five weeks after grafting, splenocytes from donor
B6 mice were irradiated (30 Gy), resuspended at a concentration of
1 x 106 in 10 µl phosphate-buffered
saline (PBS), and injected into the right ear pinnae of hosts.
PBS was injected as a control in the left ear pinnae. After 24 hours,
ear thickness was measured with a low-pressure micrometer (Mitsutoyo,
Tokyo, Japan). DTH-dependent ear swelling was calculated according to
the following formula: specific ear swelling = [(24-hour
measurement of right ear - 0-hour measurement of right ear) - (24-hour measurement of left ear - 0-hour measurement of left
ear)] x 10-3 mm. Similar
measurements were made at 48 hours. All measurements were performed in
a masked fashion, and all experiments were repeated at least once. The
unpaired t-test was used to compare the DTH responses.
P < 0.05 was considered significant.
Transplantation of LNs to the Cervical Lymphatic Chain and Analysis
of Lymph Flow
Cervical and facial LNs, or popliteal and inguinal LNs, were
harvested from BALB/c mice for transplantation to the cervical
lymphatic chains of CLN- mice to derive
reconstituted CLN-/+ mice, as previously
described.7
In summary, donor LNs were aseptically
collected by use of an operating microscope and placed on chilled
sterile RPMI 1640 until transfer to another mouse. After the mice were
anesthetized and the bilateral CLNs removed, as detailed earlier, to
derive CLN- mice, mice were reconstituted by
placing either orthotopic (CLN) or heterotopic (inguinal or popliteal)
LNs onto to each side of the trachea of CLN-
mice, thereby deriving CLN-/+ mice. In all
cases, one LN was placed on either side of the cervical lymphatic
chain, as previously described.7
To determine whether there is afferent lymphatic flow from the eye to the grafted LNs, 5 µl (25 µg/5 µl) tetramethyl rhodamine isothiocyanate (TRITC; Sigma, St. Louis, MO) was injected into the subconjunctival space of one (right) eye of reconstituted CLN-/+ mice at 2, 4, and 8 weeks after LN transplantation. One hour after TRITC injection, the (native or grafted) CLNs were removed and embedded in optimal cutting temperature (OCT) compound (Miles, Elkhart, IN). Frozen specimens were sectioned at 9 µm by cryostat. The tissues were mounted on glass slides and observed for fluorescence by a fluorescence microscope. LNs of mice that received subconjunctival injections of PBS instead of TRITC were used for negative control animals, and naïve CLN+ mice served as positive control animals (n = 5 LNs per group). The amount of TRITC in the LNs, as a measure of afferent lymph flow, was graded in a masked fashion and without knowledge of the source of the LNs in each of 10 sections through the center of the node per time point studied. The number of TRITC+ cells per x200 field were averaged for each time point.
Harvesting of CLNs for Transplantation into BALB/c Mice from
Syngeneic Corneal Graft Recipients
Once we established how long it took (4 weeks, as detailed
later) to re-establish normal lymphatic flow from the eye to grafted
LNs in CLN- mice, we sought to determine the
effect of grafting LNs from hosts of either rejected or accepted
corneal grafts to syngeneic CLN- mice to create
reconstituted CLN-/+ hosts that subsequently
received allogeneic corneal grafts. Accordingly, BALB/c mice that
received either accepted or rejected C57BL/6 corneal grafts were killed
8 weeks after corneal transplantation, for harvesting of their CLNs.
The harvested LNs were then transplanted into naïve
CLN- mice, as detailed earlier. After 4 weeks,
allogeneic C57BL/6-derived corneas were orthotopically grafted to the
reconstituted CLN-/+ hosts and observed for 12
weeks for graft survival.
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Results |
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Clinical Course of Corneal Allografts in Reconstituted Mice
The data presented demonstrate the association between failure in
induction of allospecific DTH and enhanced graft survival in
CLN- mice and the reestablishment of normal
lymphatic flow to LNs grafted to the cervical chain. To confirm that it
is the presence of LNs per se that promotes alloreactivity,
reconstituted (CLN-/+) mice were derived by
grafting syngeneic LNs to the cervical chain of
CLN- mice. Moreover, to determine whether the
contribution of CLNs to alloimmunity is site specific, both orthotopic
(cervical) and heterotopic (inguinal–popliteal) nodes were harvested
for transfer as detailed. Because we had established that it takes 4
weeks for reestablishment of lymphatic flow to the grafted LNs,
CLN-/+ mice became hosts to C57BL/6 corneal
allografts 4 weeks after LN transplantation (Fig. 3)
. Kaplan–Meier survival analysis revealed that reconstituted
CLN-/+ mice experienced rejection of their
corneal allografts in a manner indistinguishable from that in intact
CLN+ control animals, irrespective of the origin
of the grafted LNs. Accordingly, allografts were rejected in 5 (50%)
of 10 of the reconstituted CLN-/+ mice receiving
orthotopic LNs and in 7 (58%) of 12 CLN+ hosts
receiving heterotopic LNs. In either case, the rapidity and rate of
corneal graft rejection was identical with that seen in
CLN+ control animals.
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Allospecificity of CLN Transplantation
We conducted several experiments to ensure that the response
generated in reconstituted mice after LN grafting was allospecific.
Naïve BALB/c animals receiving CLNs from hosts that had
rejection of their B6 grafts were challenged, either with
C57BL/6-derived or third-party C3H-derived splenocytes (Fig. 5)
. Negative control animals were naïve, and positive control
animals were BALB/c mice that were SC immunized to either B6 or C3H
antigens before challenge. Ear swelling was measured at 24 and 48 hours
after challenge in all cases to assay for allospecific DTH.
CLN-/+ hosts reconstituted with CLNs from mice
that had shown rejection of B6 corneal grafts exhibited strong
allospecific DTH to a B6 splenocyte challenge similar to that seen in
positive control animals (Fig. 5A
, P < 0.05). By
contrast, the DTH response of similarly reconstituted mice to
third-party C3H splenocytes was indistinguishable from that seen in
negative control animals and was significantly lower than in positive
control animals (Fig. 5B
, P < 0.0002).
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Discussion |
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However, the totality of immune mechanisms involved in downmodulating the immune response to ocularly delivered antigens is still insufficient to entirely suppress the generation of T-helper 1 (Th1) cell–mediated alloimmunity.13 14 15 In fact, Sonoda and Streilein16 and Yamada et al.18 have shown that recipients of corneal grafts universally acquire donor-specific DTH within several weeks of transplantation. It is interesting, however, that although generation of DTH alloreactivity does not necessarily lead to graft rejection,10 14 15 16 several laboratories have independently shown that strategies that suppress induction of donor-specific DTH are very effective in promoting corneal graft survival.14 18 19 These observations have led us18 19 and others14 15 to conclude that generation of allospecific DTH is probably a necessary, albeit insufficient, facet of allorejection, because not all hosts that are sensitized eventually have rejection of their corneal grafts. Corneal transplant rejection ultimately also requires effective recruitment of primed alloreactive Th1 cells to the ocular anterior segment.12 15 Critical facets of ocular immune privilege, however, such as generation of regulatory cells in the spleen and active CD95-mediated killing of alloreactive T cells in the ocular microenvironment can temper the allodestructive response in the host,11 13 16 20 21 thereby offering corneal grafts a better chance of success than that of other solid organ transplants.
The classic work of Billingham et al.22 demonstrated the critical role of draining LNs in skin alloimmunity years before the specific role of T cells in solid organ graft rejection was appreciated. It is therefore surprising that, until recently, very little attention has been paid to the role of the draining LNs in the immunity generated in response to corneal transplantation. It is known that the unique immune response generated to ocularly delivered antigens, including corneal transplants, is due, at least in part, to ocular antigens and antigen-presenting cells (APCs) bypassing the lymph nodes and gaining access to the systemic (venous) blood supply and priming tolerogenic cells in the spleen.13 23 24 Although Ksander et al.9 have clearly demonstrated generation of self-restricted donor minor histocompatibility (H)–reactive cytotoxic T cells in the draining LNs of high-risk murine corneal allografts, other studies have failed to demonstrate an important role for cytotoxicity in corneal graft rejection,15 25 26 and the contribution of these observations to transplant rejection therefore remains unclear.
More recently, Kuffova et al.27 have demonstrated a CD40-dependent dendritic cell–driven activation of host T cells after murine corneal transplantation, but the antigen specificity of these cells or their functional role in corneal graft rejection have not yet been elucidated. Therefore, although generation of an alloresponse in the draining LNs of eyes after corneal transplantation is now established, its contribution to graft rejection is still poorly understood. Our data from CLN- mice clearly demonstrate that corneal grafts in mice devoid of draining LNs enjoyed universal and indefinite survival (Fig. 1) . The enhanced survival of grafts in CLN- hosts is associated with failure in the induction of allospecific DTH reactivity (Fig. 2) . Taken together with the observation by other laboratories that DTH-mediated mechanisms are critical in the rejection of corneal allografts,10 13 14 15 16 18 25 26 our data suggest that the generation of allospecific and graft-destructive DTH is dependent on functional lymphatic flow to the draining CLNs. It is now clearly established, by the work of several groups associated with the laboratories of Niederkorn11 14 26 and Streilein13 23 24 28 that regulatory allospecific graft-protective responses are generated in the spleen after corneal transplantation, and that disruption of the oculosplenic axis can have a deleterious effect on graft outcome, as reflected by our data demonstrating enhanced graft rejection rates in splenectomized hosts compared with either naïve control animals or CLN- hosts (Fig. 1) .
The strong link between draining CLNs and generation of DTH-type allodestructive immunity, and not tolerance, is supported, not only by data demonstrating universal graft survival in CLN- mice, but also by our observation (data not shown) of an intact ACAID response to ocular antigens in CLN- mice, suggesting that LN-deficient mice are still competent in the promotion of tolerance to intracameral antigens. Thus, we explain the enhanced survival of allografts in CLN-/Sp- hosts by proposing that the interruption of the normal lymphatic drainage from the eye in these hosts and thus of allosensitization, as reflected by failure in generation of donor-specific DTH, circumvents the critical need for (spleen-dependent) induction of tolerance in promoting graft survival and thereby renders CLN-/Sp- hosts less susceptible to any deleterious effect of splenectomy per se on transplant survival (Fig. 1) .
Finally, reconstitution of CLN- mice by transfer of LNs from hosts with corneal grafts of long-standing acceptance failed to demonstrate any added protection from corneal graft rejection compared with normal naïve hosts (Fig. 4) . Conversely, reconstitution with LNs from hosts that had rejection of their corneal grafts led to swift rejection of subsequent corneal transplants, suggesting successful adoptive transfer of allodestructive, but not alloprotective, responses. As such, transfer of Th1-mediated alloreactivity by LN reconstitution is similar to the adoptive transfer of allospecific tolerance to naïve mice by transfer of ACAID-inducing splenic cells from hosts with long-standing accepted grafts as described by Streilein,24 Niederkorn,26 and Sano et al.28
Notwithstanding the evidence from our data that relates draining LNs to allosensitization, we cannot theoretically rule out the possibility that a population of regulatory T cells may still be generated in the LNs that migrate subsequently to other secondary lymphoid organs, including the spleen, for expansion and recirculation. Because we tested the effect of reconstituting mice with LNs derived from hosts with graft acceptance 8 weeks after surgery (and noted no difference in subsequent corneal graft survival compared with naïve hosts), it is possible that the functional contribution of these putative LN-derived regulatory cells could not be assayed so late after transplantation, because these cells may have already entered the systemic circulation.
We found that nodes transplanted to the cervical chain demonstrate re-established normal afferent lymph flow from the eye by 4 weeks after transplantation. This differs only slightly with the findings of Wolvers et al.,7 who reported that it takes 3 weeks to recover normal afferent flow from the nasal mucosa to grafted CLNs. However, they determined that the cervical nodes that directly drain the nasal mucosa, but not the peripheral nodes, constitute a unique environment that favors immunologic tolerance to nasally administered antigens. Perez et al. have recently shown that there is impaired induction of Th1 response in the draining LNs of eyes intracamerally injected with soluble antigen.29 These findings are in contrast to the data presented herein, with which we have shown that draining cervical LNs, regardless of their origin, demonstrate alloimmune responses including allospecific DTH and graft rejection.
The reasons that the draining LNs in one instance (in response to soluble antigens introduced through the nasal mucosa or anterior chamber) are related to tolerance and in the other (in response to transplantation antigens in corneal allografts) to Th1 immunization cannot be directly addressed by our data. It is possible that obvious differences between the soluble antigens (e.g., ovalbumin) tested by both Wolvers et al.7 and Perez et al.29 and transplantation antigens operative in our model profoundly affect the nature of the immune response generated.30 This is not altogether unlikely: Recent studies in our laboratory31 have shown that induction of tolerance to transplant antigens is more difficult than to soluble antigens injected into the anterior chamber.
In summary, in contrast to the extensively studied oculosplenic venous-dependent antigen and APC traffic that primes tolerance to ocular antigens, our data implicate functional flow to draining CLNs as a necessary component of alloimmunity and graft rejection in corneal transplantation. Further studies are required to better characterize the molecular facets of immunity that lead to allodestructive immunization in the case of draining LNs and transplant tolerance in the case of the spleen.
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Footnotes |
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Submitted for publication September 14, 2000; revised January 12, 2001; accepted January 24, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: M. Reza Dana, Laboratory of Immunology, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. dana{at}vision.eri.harvard.edu
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