| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Immunology and Glickman Urologic Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The specific factors that define whether antidonor T cell immunity is induced following transplantation and whether this induced response will be pathogenic are not well understood. The number and activation state of graft-derived dendritic cells capable of priming recipient T cells (13, 14), the presence of ischemia-reperfusion injury to the graft (15, 16), and the number of foreign Ags expressed by the graft (11, 17) are among the donor characteristics that may contribute to the immunogenicity of a transplanted organ. Once the recipient T cells are activated, potentially relevant factors that determine whether these lymphocytes will induce graft destruction include the quantity and distribution of Ag expressed on the individual graft cells (4, 5, 17, 18), the subtype (CD4 vs CD8) of T cells activated in response to the transplant (19), the specific chemoattractant molecules that recruit T cells to graft site (2, 3), the effector functions utilized by the activated T cells when they re-encounter their ligand at the graft site (cytokines produced, cytotoxicity) (4, 8, 9, 17, 18, 20, 21), and the frequency of effector T cells induced (11, 17, 22).
Transplantation of a fully allogeneic organ graft primes a high frequency of donor-reactive CD4+ and CD8+ T cells capable of mediating cytotoxic lymphocyte (CTL) activity and producing type 1 proinflammatory cytokines (e.g., IFN-
) (9, 17, 21, 23, 24). Untreated recipients rapidly reject fully allogeneic heart and skin grafts (10, 11, 22). In contrast, minor Ag-disparate transplants prime lower frequencies of effector T cells, often with the same proinflammatory phenotype as T cells induced to a fully allogeneic graft (7, 10, 17, 22, 25, 26). Nonetheless, such minor Ag-disparate grafts are rejected at a slower pace than MHC-disparate grafts, and in some situations minor Ag-disparate transplants are not rejected at all (7, 10, 17).
Although the frequency of induced effector T cells seems to influence the outcome of a transplanted organ, it has been suggested that the size of the target organ might also contribute to the resultant pathology (11, 27, 28). Proinflammatory, cytolytic, and Th1 cytokine-producing effector T lymphocytes have limited life spans and limited capacities to kill target cells. Thus, larger grafts may be more resistant than smaller grafts to the consequences of a defined number of activated donor-reactive effector T cells. Selected studies suggest that this may indeed be true (11, 27, 28), but a detailed assessment of the interrelationship between T cell frequency and graft size has not been performed.
In an effort to better understand these relationships, we performed a series of experiments using minor Ag-disparate skin and heart transplantation in mice. We found that skin and heart grafts prime similar numbers of donor-reactive effector T cells and that a threshold number of these effector T cells is required to result in graft destruction. Consistent with previous work, larger numbers of effector T cells are required to destroy a heart vs a skin graft derived from the same donor strain. Our data additionally show, however, that given a limited antidonor T cell repertoire, it is the tissue mass of the graft rather than the type of graft (skin vs heart) that determines whether the graft is accepted or rejected. Finally, the data show that even in the absence of graft destruction, low frequency antidonor T cell immunity has adverse effects on the target organ and contributes to chronic graft injury.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Male and female C57BL/6 (H-2b) and A/J (H-2a) mice, age 6–8 wk, were purchased from The Jackson Laboratory (Bar Harbor, ME). Female C57BL/10NA;-(Tg)TCR MataHari-(KO) Rag1 (H-2b, MataHari RAG KO) (4), age 6–8 wk, were obtained as a generous gift from P. Matzinger (National Institutes of Health, Bethesda, MD) and O. Lantz (Institut National de la Santé et de la Recherche Médicale, Paris, France). Female MataHari RAG+/- mice were obtained as the F1 generation of a cross between MataHari RAG KO mice and wild-type B6 animals. All animals were maintained and bred in the pathogen-free animal facility at the Cleveland Clinic Foundation.
Peptides
HYDbyp (NAGFNSNRANSSRSS), HYUtyp (NAGFNSNRANSSRSS), and 
gal96–103 (DAPIYTNV) were synthesized by Research Genetics (Huntsville, AL) at >90% purity.
Placement and evaluation of skin and cardiac grafts
Full-thickness trunk skin grafts were placed using standard techniques (17, 23). Bandages were removed on day 7, and the grafts were then visually scored daily for evidence of rejection. Grafts were considered fully rejected when they were >90% necrotic. Vascularized heterotopic cardiac grafts obtained from 8- to 10-wk-old donors were placed in the abdomen as described and palpated daily for evidence of a heartbeat (4, 8, 29). For selected experiments, donor hearts were obtained from 3-wk-old donors. Rejection was defined as a loss of palpable heartbeat. Technical failures were defined as loss of heartbeat within 48 h of graft placement. Technical failure rate was <10% for standard heart grafts, but was 
40% in recipients of small, 3-wk-old donor hearts. Grafts were harvested at the time of rejection or at predetermined time points posttransplant.
Histology and immunohistochemistry
Formalin-fixed paraffin sections of graft tissues were stained with H&E and for elastin as described elsewhere (4, 8, 29). Vasculopathy was quantified by calculating the neointimal index (NI) as described by Armstrong et al. (30, 31) and by reporting the number of vessels with >30% vasculopathy per graft.
ELISPOT assays
Assays were performed as outlined previously in detail (4, 22, 29, 32). Briefly, ELISPOT plates (Millipore, Bedford, MA) were coated overnight with the capture Abs (obtained from BD PharMingen, San Diego, CA) in sterile PBS, blocked with sterile 1% BSA in PBS, and washed three times with sterile PBS. Spleen cells (0.2–1 x 106/well) were plated in HL-1 medium (BioWhittaker, Walkersville, MD) with or without mitomycin C-treated male stimulator cells (400,000/well) and/or soluble Ags (HYDbyp, HYUtyp, gal96–103 at 0.1–10 µM) and then incubated at 37°C in 5% CO2 for 24 h. After washing with PBS followed by PBS/0.025% Tween (PBST), detection Abs (obtained from BD PharMingen) were added overnight. After washing with PBST, alkaline phosphatase-conjugated anti-biotin Ab (Vector Laboratories, Burlingame, CA) diluted 1/2000 in PBST was added for 90 min at room temperature. The plates were developed as previously described (4, 22, 29, 32). The resulting spots were counted on an ImmunoSpot Series 1 Analyzer (Cellular Technologies, Cleveland, OH).
In vivo CTL assays
This assay was adapted from published studies (33). Spleen cells were isolated from naive B6 females and RBCs were removed by osmotic lysis. The B6 spleen cells were suspended in RPMI 1640 plus 10% FBS at 10 x 106/ml and pulsed with HYUtyp (experimental) or gal96–103 (control), 2 µg/ml final concentration for 90 min at 37°C in 5% CO2. After washing five times in PBS, cells were resuspended at 10 x 106/ml in PBS/0.1% BSA. The control peptide-loaded cells were labeled with a high concentration of CFSE (20 µM) (CFSEhigh cells) and the HYUtyp-loaded target population was labeled with a low concentration of CFSE (3 µM) (CFSElow cells) for 10 min at 37°C in 5% CO2. The labeled cells were washed three times in PBS. Equal numbers of cells from each population were mixed together and injected i.v. into the tail vein of recipient mice at predetermined time points posttransplantation. Injections were performed such that each mouse received a total of 5 x 106 experimental (CFSElow) cells and 5 x 106 control (CFSEhigh) cells in a total of 400 µl of PBS. Sixteen hours later, the animals were sacrificed and the cell suspensions were analyzed by flow cytometry. Each population was detected by its differential CFSE fluorescence intensities. Up to a total of 500,000 gated events were acquired per sample. For each animal, we calculated a ratio of the number of CFSElow cells to the total number of CFSElow plus CFSEhigh cells. Specific lysis was calculated as (1 - (ratio in naive B6 mice - ratio experimental mice)) x 100.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ELISPOT recall responses for spleen cells obtained from individual skin or heart graft recipients. Spleen cells from naive mice were included as controls. We tested for reactivity to two known immune dominant determinants derived from the male Ag (36, 37), HYDbyp (MHC class II, I-Ab-restricted) and HYUtyp (MHC class I, Db-restricted), and for reactivity to mitomycin C-treated donor male spleen cells. The frequency of donor-reactive CD4+ and CD8+ T cells specific for male Ags was of similar magnitude in heart and skin graft recipients. Although placement of a skin graft induced a significantly higher frequency of donor-reactive IFN--producing T cells (200–250 per/million donor-reactive cells) than heart graft recipients (100–150 per million), this difference was only 2-fold, could be partially attributed to differences in kinetics of activation (see Fig. 3), and was of unclear biologic significance. For comparison, the frequency of antidonor T cells induced in response to fully allogeneic transplanted hearts or skin grafts (both acutely rejected) is 10- to 20-fold higher than to the minor Ag-disparate grafts (Fig. 2A and Refs. 22 and 29). Immune cells from skin or heart graft-primed mice did not produce IL-4 or IL-5 and did not respond to control peptide -gal96–103 (data not shown). No anti-HY immunity was detectable in naive B6 females (Fig. 2A).
|
|
|
gal96–103 or specific target cells loaded with HYUtyp are labeled with different concentrations of CFSE so that they can be differentiated by flow cytometry (a 5-fold concentration difference permits distinguishing between the two populations). For our experiments, the HYUtyp-loaded targets cells were labeled with CFSElow and the control syngeneic cells were labeled with CFSEhigh. Equal numbers of the two populations (5 x 106 of each) were then mixed and injected i.v. into the tail vein of a naive or a grafted mouse. Animals were sacrificed the following day (<16 h) and spleen cells were studied by flow cytometry for the presence of the CFSE-labeled cells. As shown in Fig. 2B, skin and heart grafts both induced potent antimale CTL activity compared with naive controls. Thus, on day 14 posttransplant, the frequency, cytokine profile, ability to mediate cytotoxicity, and relative immune dominance of the antimale T cell immune response did not differ substantially between skin and heart graft recipients. Nevertheless, skin grafts were rapidly rejected but heart grafts were not (Fig. 1).
We next performed a kinetic analysis of T cell immune function and graft histopathology following transplantation of male heart grafts to syngeneic female recipients. As shown in Fig. 3, anti-HY T cell immunity was readily detectable on days 7–14 posttransplant. The immune response to the MHC II-restricted peptide peaked on day 7, several days before the detected response to the dominant MHC class I-restricted peptide (as assessed by IFN- ELISPOT (Fig. 3A) and in vivo CTL activity (Fig. 3B). Both antidonor CD4+ and CD8+ T cell immunity rapidly diminished by days 21–30 posttransplant.
Kinetic histologic evaluation revealed a diffuse intragraft infiltrate detectable in male hearts placed into female recipients on days 7–21 but few mononuclear cells were detectable in the recipients by day 30 (Fig. 4). Male heart grafts exhibited early vasculopathy on day 60 posttransplant and progressive vasculopathy by day 90. Quantitative analysis revealed significantly increased frequency and severity of transplant vasculopathy in male hearts transplanted into females when compared with isogenic female heart grafts placed into female recipients by day 90 posttransplant (Table I). The female grafts exhibited an essentially normal histologic appearance. The progressive vasculopathy in male but not female grafts suggested that the female recipients of male heart grafts were not tolerant to male transplantation Ags.
|
|
ELISPOTs (frequency) and in vivo CTL assays (Fig. 5), confirming the absence of tolerance. In striking comparison, there was minimal detectable antimale immunity in B6 female recipients of B6 male hearts grafts alone on days 50–60 (no additional skin graft placed, Fig. 5).
|
An additional possibility that could account for the absence of rapid graft destruction (persistent graft function) in female recipients of male hearts is that amount of male Ag expressed on the parenchymal cells of the graft might be too low to be recognized by primed T cells trafficking through the organ. To assess this possibility, we placed male B6 heart grafts into female MataHari RAG KO recipient mice. MataHari females bred onto a B6 RAG KO background are TCR-transgenic animals in which every T cell in the recipient is CD8+ and specific for the immune dominant determinant HYUtyp plus Db (4). As shown in Fig. 6, MataHari RAG KO females rapidly rejected the male (but not female) B6 heart grafts. As might be anticipated for a TCR-transgenic RAG KO recipient, the rejection was associated with a high frequency of primed antidonor effector T cells as assessed by IFN- production at the time of rejection (>11,000 per million spleen cells, n = 3, data not shown). These results demonstrate that the male grafts do express sufficient Ag to facilitate rejection by primed T cells if large enough numbers of these effector T cells are present in the recipients.
|
20% MataHari T cells (data not shown) with the remainder of the CD8+ and CD4+ T cell repertoire deriving endogenously. Despite the increased frequencies of donor-reactive T cells compared with wild-type female B6 recipients (Table II), the MataHari RAG+/- recipients did not acutely reject male B6 heart grafts. The grafts transplanted into these animals did, however exhibit clear evidence of chronic injury/vasculopathy by an early 30-day time point (Fig. 6 and Table I). ELISPOT recall assays performed on days 7 and 30 posttransplant revealed 10- to 50-fold higher absolute numbers of antidonor effector T cells compared with wild-type B6 recipients (Table II). Overall, the ability of MataHari RAG KO females to reject male heart grafts is consistent with the interpretation that a threshold number of T cells is required to acutely reject a cardiac transplant (11). The data further suggest that subthreshold numbers of donor-reactive T cells mediate chronic injury and that the severity and rapidity of the induced injury is partially dependent on the frequency of donor-reactive T cells in the recipient; below the threshold number that leads to acute organ destruction, higher frequencies of donor-reactive T cells induce chronic injury at a more rapid rate than lower frequencies.
|
60% of the technically successful small heart transplants were acutely rejected by day 25 (Fig. 7). Immune-mediated injury was confirmed by histologic examination in all grafts that stopped beating (Fig. 7). Recall immune responses on day 14 posttransplant revealed that the frequency of antidonor T cells was no higher in recipients of small vs large heart grafts (10–60 per million HYUtyp-specific IFN- producers and 30–300 per million HYDbyp-specific IFN- producers, n = 5, data not shown), showing that transplantation of small vs large hearts was no more efficient at priming recipient T cells. Thus, the data are consistent with the interpretation that the ability of a given number of effector T cells to reject a target organ is largely dependent on the size of the organ.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We did find more antidonor T cells in the skin vs heart graft recipients, consistent with the interpretation that skin is more immunogenic than heart tissue. Still, the highest detectable frequencies were much below the frequency of antidonor T cells induced in response to a fully allogeneic graft (Fig. 2) and could in part be related to differences in activation kinetics following skin vs heart transplantation. More importantly, even a >10- to 50-fold increase in the frequency of donor-reactive effector T cells as found in the MataHari RAG+/- recipients (Fig. 6 and Table II) did not result in acute rejection of male heart grafts. Thus, the detected difference in the frequency of antidonor IFN--producing T cells in skin vs heart graft recipients was of unclear biologic significance and alone could not account for the difference in graft outcome between the two sets of recipients. Also, there was no significant difference in the relative immunodominance of MHC class I-restricted or MHC class II-restricted anti-HY responses between skin and heart transplant recipients (Fig. 2). Nor was there a difference in the development of type 1 cytokine secretion or the ability to mediate CTL activity in recipients of heart vs skin grafts at 7–14 days posttransplant. Thus, our data strongly suggest that the immunogenicity of the donor graft alone cannot account for the difference in outcome between skin and heart grafts in this model.
The results delineated by this work raise the possibility that one major difference between skin and heart grafts occurs not at the priming stage, but instead at the effector stage. The larger amount of tissue found in the heart vs the skin grafts seems to resist destruction by a limited T cell repertoire. This conclusion is supported by experiments showing that adequate Ag is expressed on heart tissue to permit graft destruction if sufficient numbers of high-affinity antidonor T cells are present in the recipient (Fig. 6). Additionally, female recipients rejected small male heart grafts despite the fact that they did not prime higher numbers of anti-HY T cells than the larger grafts. Complementary experiments further showed that increasing the amount of skin graft tissue resulted in prolonged graft survival despite priming of the same frequency of donor-reactive T cells as single graft recipients (Fig. 8). The results confirm and extend previous studies in heart and skin graft models suggesting that the size of the graft tissue can influence graft survival (11, 27, 28). Importantly, these previous studies did not assess whether the noted effect of tissue burden was attributable to T cell priming or an influence at the effector stage issue, an issue clarified by this work.
Our data also confirm, using a polyclonal system, the findings of Jones et al. (11) in which the authors demonstrated that a threshold number of TCR-transgenic T cells are required to reject an allograft and that this threshold number is larger for heart vs skin grafts. The data from the present manuscript provide additional insight by showing that a subthreshold number of donor-reactive T cells, while not capable of acutely rejecting the graft, induce chronic graft injury as manifested by fibrosis and transplant vasculopathy (Figs. 4–7 and Table I). Male-to-female heart grafts exhibited evidence of vasculopathy at 60–90 days posttransplant, while syngeneic female-to-female hearts were essentially normal at this time point. If the frequency of antidonor effector T cells was increased, but remained below the threshold required for rejection, chronic injury occurred at an accelerated rate; vasculopathy was detectable by day 30. This was true for both monoclonal TCR-transgenic T cells and for polyclonal effector T cells boosted by a skin allograft. It is important to note that no anti-HY Abs develop in this model and essentially no vasculopathy was detectable in syngeneic female transplants. The resultant vasculopathy can therefore only be attributed to antidonor (anti-HY) T cell immunity.
These findings have important implications for human transplantation and suggest that understanding and monitoring the frequency of donor-reactive T cells may be relevant to predicting long-term graft function in a clinical setting. In many respects, the concept of antidonor T cell frequency as a risk for long-term outcome is reminiscent of the relationship between elevated blood pressure and chronic organ injury (45, 46). Extremely high blood pressure can result in acute injury (encephalopathy, renal failure, heart failure) but subthreshold elevations in blood pressure produce chronic injury to the same organs. Moreover, the risk of chronic injury is directly related to the level of blood pressure and the time over which the blood pressure is elevated. Analogously, our data, in conjunction with recently published work by our group in human allograft recipients (47, 48), suggest that the frequency of donor-reactive T cells in the recipient over time may directly correlate with the risk of developing chronic injury.
One additional issue that we found particularly intriguing was the observation that although anti-HY T cell immunity was induced by heart grafts, the immune response was not sustained in wild-type recipient mice. Understanding in detail why such potent immunity rapidly exhausts is an important issue that could potentially be exploited to prolong allograft survival in other situations. One potential interpretation is that each effector T lymphocyte has a limited life span and a limited ability to kill a certain number of target cells. Once that limit is reached, the T cell dies. The number of donor Ag-expressing cells in a heart graft (but not a skin graft) may be sufficiently large to withstand the initial onslaught, with the result being sublethal injury without graft destruction. New thymic immigrants would only be primed inefficiently, as the number of donor APCs capable of priming naive T cells is markedly reduced over time. If an additional immunogenic stimulus such as a skin graft is placed, then the new T cells (or memory T cells) expand, reject the skin graft, and produce additional injury to the male heart. Overall, such a model is analogous to the inadequate immune response induced to a chronic viral infection where the initial infection primes a response, but this antiviral immunity becomes "exhausted" over time (49, 50). Vaccination in the correct context can boost the response and cure the infection.
An alternate but not mutually exclusive explanation for the observed decrease in antidonor immunity beyond 3 wk following heart transplantation is that regulatory T cell responses develop as a natural means of controlling the induced response. It has been hypothesized that one mechanism to control any immune response is the coincident increase in regulatory T cells (Treg) (51, 52, 53). Although detailed mechanisms are not understood, it is clear that Treg expand in concert with most proinflammatory immune responses and it is thought that such regulatory cells may be essential down-modulators of the immune system. The natural activation and expansion of Treg following heart transplantation might be able to control a low frequency response to a minor Ag-disparate heart graft, but be inadequate to control the high frequency responses induced to a fully MHC-disparate allograft. Depletion of anti-CD25+ CD4+ T cells in vivo can result in minor Ag-disparate heart graft rejection accompanied by an increase in antidonor T cell immunity (54), consistent with this hypothesis.
In summary, the results from these studies clarify an important interrelationship between T cell frequency and size of a target organ. A threshold number of T cells is required to reject a heart graft, and this number is dependent in part on the tissue burden of the target organ. Subthreshold numbers of effector T cells, while insufficient to acutely destroy the graft, induce chronic injury in a frequency- and time-dependent manner. The findings provide an experimental basis for the clinical observation that graft function in human recipients of transplants with larger tissue mass is better than in recipients of allografts with smaller tissue mass (55, 56). Moreover, the studies highlight the need for immune monitoring in human allograft recipients so as to be able to maintain the antidonor immune response at levels that are as low as possible without inducing significant side effects.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Peter S. Heeger, Department of Immunology, Cleveland Clinic Foundation, NB30, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: heegerp{at}ccf.org
3 Abbreviations used in this paper: NI, neointimal index; Treg, regulatory T cell.
Received for publication August 13, 2003. Accepted for publication October 20, 2003.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2-microglobulin as a minor transplantation antigen involves multiple effector pathways: role of Fas-Fas ligand interactions and Th2-dependent graft eosinophil infiltrates. J. Immunol. 169:500.. Transplantation 69:1016.[Medline]
: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions. J. Immunol. 166:3248.-induced chemokine Mig. J. Immunol. 163:4878. independently predicts renal function in kidney transplant recipients. Am. J. Transplant. 3:878.[Medline]
/ and interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75:8407.This article has been cited by other articles:
|
|
 |
|
  T. Nozaki, J. M. Rosenblum, D. Ishii, K. Tanabe, and R. L. Fairchild CD4 T Cell-Mediated Rejection of Cardiac Allografts in B Cell-Deficient Mice J. Immunol., October 15, 2008; 181(8): 5257 - 5263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. H. Koehn, M. L. Ford, I. R. Ferrer, K. Borom, S. Gangappa, A. D. Kirk, and C. P. Larsen PD-1-Dependent Mechanisms Maintain Peripheral Tolerance of Donor-Reactive CD8+ T Cells to Transplanted Tissue J. Immunol., October 15, 2008; 181(8): 5313 - 5322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Pavlov, H. Raedler, S. Yuan, S. Leisman, W.-h. Kwan, P. N. Lalli, M. E. Medof, and P. S. Heeger Donor Deficiency of Decay-Accelerating Factor Accelerates Murine T Cell-Mediated Cardiac Allograft Rejection J. Immunol., October 1, 2008; 181(7): 4580 - 4589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. F. N. Chan, H. Razavy, and C. C. Anderson Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance J. Immunol., October 1, 2008; 181(7): 4603 - 4612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bolinger, P. Krebs, Y. Tian, D. Engeler, E. Scandella, S. Miller, D. C. Palmer, N. P. Restifo, P.-A. Clavien, and B. Ludewig Immunologic ignorance of vascular endothelial cells expressing minor histocompatibility antigen Blood, May 1, 2008; 111(9): 4588 - 4595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. F. Moxham, J. Karegli, R. E. Phillips, K. L. Brown, T. T. Tapmeier, R. Hangartner, S. H. Sacks, and W. Wong Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection J. Immunol., March 15, 2008; 180(6): 3910 - 3918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nozaki, H. Amano, A. Bickerstaff, C. G. Orosz, A. C. Novick, K. Tanabe, and R. L. Fairchild Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients J. Immunol., October 15, 2007; 179(8): 5238 - 5245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Garrod, C. K. Chang, F.-C. Liu, T. V. Brennan, R. D. Foster, and S.-M. Kang Targeted Lymphoid Homing of Dendritic Cells Is Required for Prolongation of Allograft Survival J. Immunol., July 15, 2006; 177(2): 863 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Valujskikh, Q. Zhang, and P. S. Heeger CD8 T Cells Specific for a Donor-Derived, Self-Restricted Transplant Antigen Are Nonpathogenic Bystanders after Vascularized Heart Transplantation in Mice J. Immunol., February 15, 2006; 176(4): 2190 - 2196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Krupnick, A. E. Gelman, W. Barchet, S. Richardson, F. H. Kreisel, L. A. Turka, M. Colonna, G. A. Patterson, and D. Kreisel Cutting Edge: Murine Vascular Endothelium Activates and Induces the Generation of Allogeneic CD4+25+Foxp3+ Regulatory T Cells J. Immunol., November 15, 2005; 175(10): 6265 - 6270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Kelemen and M. V. Autieri Expression of Allograft Inflammatory Factor-1 in T Lymphocytes: A Role in T-Lymphocyte Activation and Proliferative Arteriopathies Am. J. Pathol., August 1, 2005; 167(2): 619 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Heeger, P. N. Lalli, F. Lin, A. Valujskikh, J. Liu, N. Muqim, Y. Xu, and M. E. Medof Decay-accelerating factor modulates induction of T cell immunity J. Exp. Med., May 16, 2005; 201(10): 1523 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhou, S. J. Balin, M. Mashayekhi, K. W. Hwang, D. A. Palucki, and M.-L. Alegre Transplantation Tolerance in NF-{kappa}B-Impaired Mice Is Not Due to Regulation but Is Prevented by Transgenic Expression of Bcl-xL J. Immunol., March 15, 2005; 174(6): 3447 - 3453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schenk, D. D. Kish, C. He, T. El-Sawy, E. Chiffoleau, C. Chen, Z. Wu, S. Sandner, A. V. Gorbachev, K. Fukamachi, et al. Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4+CD25+ T Cells J. Immunol., March 15, 2005; 174(6): 3741 - 3748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Poggio, M. Clemente, J. Riley, M. Roddy, N. S. Greenspan, C. Dejelo, N. Najafian, M. H. Sayegh, D. E. Hricik, and P. S. Heeger Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1952 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Chalasani, Q. Li, B. T. Konieczny, L. Smith-Diggs, B. Wrobel, Z. Dai, D. L. Perkins, F. K. Baddoura, and F. G. Lakkis The Allograft Defines the Type of Rejection (Acute versus Chronic) in the Face of an Established Effector Immune Response J. Immunol., June 15, 2004; 172(12): 7813 - 7820. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
and •, Results for recipients of male hearts alone (n = 4). 
and 
, Results for recipients of male hearts that additionally received male skin grafts on day 30 following the heart transplant. No responses were detected to control peptides (data not shown). C, Representative H&E-stained and elastin-stained (inset) section of a male heart graft placed into a female recipient followed by placement of a male skin graft on day 30. The histology was assessed on day 55 after the heart transplant, 1 wk after the skin graft was visually rejected. Inset is an elastin-stained section from the same graft. Original magnification, x10.
) or B6 MataHari RAG+/- recipients (
