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The Journal of Immunology, 1999, 163: 5353-5357.
Copyright © 1999 by The American Association of Immunologists

CD4+ CD45RB Low-Density Cells from Untreated Mice Prevent Acute Allograft Rejection1

Joanna D. Davies2, Eric O’Connor, DeShon Hall, Troy Krahl, Joseph Trotter and Nora Sarvetnick

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In the absence of therapy that suppresses the action of the immune system, the immune response to transplantation Ags results in rapid rejection of the transplant. The most successful mechanism so far described that achieves organ-specific immunological tolerance is that which controls peripheral tolerance to self-tissue. Until now, no similarities have been documented between the peripheral response to self-Ags and the response to transplantation Ags. CD4+ cells that express a high density of CD45RB (in the mouse) and CD45RC (in the rat) on their surface have been shown to cause a number of autoimmune disorders. In contrast, autoimmunity caused by the CD45RB high-density cells is inhibited by CD4+ CD45RB cells that express a low density of CD45RB (CD45RC in the rat). In this paper we show that CD4+ CD45RB high-density cells are sufficient to cause rejection of a MHC-mismatched pancreas allograft, whereas CD4+ CD45RB low-density cells are not. Unexpectedly, the CD45RB low-density cells prevent the CD45RBhigh expressing cells from causing rejection. These data suggest that the response to foreign tissue can be controlled in the same way as the response to self-tissue.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Diabetes results from the destruction of the pancreas. One strategy to overcome diabetes would include the transplantation of a pancreas or islet graft. The qualities necessary for a therapy to prevent allograft rejection are the same as those required to maintain tolerance to self-tissue. The optimal outcome would be lifelong tolerance to transplantation Ags, with responsiveness to pathogens intact.

Tolerance to self is established through a number of mechanisms including deletion of self-specific cells in the thymus (1, 2, 3), and T cell deletion (4), T cell indifference (5, 6, 7), and clonal anergy (8, 9) in the periphery. CD4+ CD45RB high-density (CD45RBhigh)3 cells from an untreated murine donor (CD45RChigh in the rat) are capable of causing clinical signs of colitis (10, 11, 12, 13, 14), diabetes (15), and thyroiditis (16). In all cases where CD45RBhigh cells have been shown to cause autoimmunity, CD4+ CD45RB low-density (CD45RBlow) cells prevent the induction of the disease (10, 11, 12, 13, 14, 15, 16). Rejection of pancreas allografts is known to be induced by CD4+ T cells (17, 18, 19, 20). Moreover, murine recipients of MHC-mismatched allografts are prevented from rejecting them by treatment with a CD45RB-specific mAb that blocks the activity of CD45RBhigh cells (mAb) (21, 22). These data would suggest that the same cell subset, the CD4+ CD45RBhigh cell subset, that causes diabetes, colitis, and thyroiditis is also involved in allograft rejection.

CD45RB is a transmembrane protein tyrosine phosphatase expressed on leukocytes and involved in T lymphocyte activation (23). Its density on T lymphocytes has been used to separate T cells into functionally distinct subsets that have either pathological or nonpathological activity (10, 11, 12, 13, 14, 15, 16). In addition, although not an absolute marker for the distinction of T cells into Ag-experienced (memory, CD45RBlow) cells and Ag-inexperienced (naive, CD45RBhigh) cells, in combination with two other cell surface molecules, CD62L and CD44, it has been used to identify such subsets (24, 25, 26, 27, 28). We have investigated the possibility that CD4+ CD45RBhigh cells are sufficient to cause allograft rejection and that CD4+ C45RBlow cells are capable of inhibiting that rejection process.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

C57BL/6J (C57BL/6, H-2b) adult mice and BALB/cByJ (BALB/c, H-2d) neonates were obtained from the Scripps Breeding Colony (La Jolla, CA). C57BL/6J-SCID/SzJ (C57BL/6-SCID, H-2b) mice were purchased from The Jackson Laboratory (Bar Harbor, ME).

Grafting of neonatal pancreata

Pancreata of BALB/c (H-2d) neonates were grafted under the kidney capsules of C57BL/6-SCID males (H-2b).

Histological assessment

Grafts were fixed in 10% neutral buffered formalin and embedded in paraffin. Sections (4 µm) were stained with hematoxylin and eosin for histological examination or were tested for the presence of insulin by immunohistochemistry as described (29). The area encompassed by islets and cellular infiltration was measured using a Leica Image Processing and Analyzing System (Q500 MC; Leica, Cambridge, U.K.). Statistical analysis was performed using InStat version 2.0 for Macintosh. Data were analyzed using ANOVA, then the Bonferroni Multiple Comparison Test (30). A p value <=0.05 is considered significant.

Cellular infiltration

In some experiments mice will receive two grafts. The first is given at the time of the cell infusion; the second is given 6 wk later. For first grafts, those that were scored positive for cellular infiltrates were infiltrated in 75–100% of the tissue. Those grafts that were scored negative for cellular infiltrates showed 0% cellular infiltration. For second grafts, those that were scored positive for cellular infiltrates showed infiltration in 12–100% of the graft. Grafts which scored negative for cellular infiltrates showed 0% infiltration.

Cell purification

Spleen cells from 2- to 4-mo-old C57BL/6 male mice were prepared for single cell suspensions. RBC were removed with lysing buffer (Sigma, St. Louis, MO), and the remaining spleen cells were resuspended in PBS with 1% FBS (Intergen, Purchase, NY). Splenocytes were labeled with a PE-conjugated CD4-specific mAb, GK1.5 (Becton Dickinson, Mountain View, CA) (31), and a FITC-conjugated CD45RB-specific mAb, MB23G2 (PharMingen, La Jolla, CA) (32), and sorted under high speed on a FACSVantage SE with TurboSort (Becton Dickinson Immunocytometry Systems, Mountain View, CA). The CD45RBhigh and CD45RBlow populations are defined as the brightest-staining 30% and dullest-staining 15% of the CD4+ cells, respectively. All cell populations were sampled and analyzed using FACSCalibur with CELLQuest version 3.2 software (Becton Dickinson Immunocytometry Systems) to determine the purity of the sorted populations (Fig. 1Go). CD4+ CD45RBhigh and CD4+ CD45RBlow populations used were >98% CD4+ (data not shown). Cell subsets were washed in PBS once after sorting but before i.v. injection into recipients.



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  		FIGURE 1. Two subsets of CD4+ cells are purified on the basis of the density of cell surface CD45RB, which they express. The figure shows the density of CD45RB expression on CD4+ cells after staining with FITC-labeled CD45RB-specific mAb. a shows the fluorescence intensity of CD45RB staining before sorting, and b shows the fluorescence intensity of the purified CD45RBlow and CD45RBhigh cells.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
CD4+ CD45RBhigh but not CD4+ CD45RBlow cells reject a pancreas allograft

To determine whether CD45RBhigh cells can cause the rejection of a pancreas allograft, C57BL/6J-SCID mice were grafted with a pancreas from a 1-day-old BALB/c donor and infused with 0.25 x 106 CD4+ CD45RBhigh cells, 0.25 x 106 CD4+ CD45RBlow cells, or no cells. The grafts were assessed histologically, and the area encompassed by islets and cellular infiltration was determined. C57BL/6-SCID mice that were infused with CD4+ CD45RBhigh cells rejected 70% of the allografts within 3 wk after transplantation (Fig. 2Goa). The grafts contained massive cellular infiltration (Fig. 2Goe) and a reduction in islet area compared with the group that received either CD45RBlow cells (p < 0.01) or no cells (p < 0.05, Fig. 2Gof). In contrast, only 1 of 10 of the grafts harvested from mice that received an equal number of CD4+ CD45RBlow cells displayed any signs of rejection (Fig. 2Gob). As expected, none of the grafts (0 of 7) from mice that did not receive a cell infusion showed signs of rejection (Fig. 2Goc). The infusion of fewer CD4+ CD45RBhigh cells (0.125 x 106) resulted in a much lower incidence of allograft rejection (data not shown). In contrast, the infusion of 0.5 x 106 CD45RBhigh cells resulted in a similar incidence of rejection as with 0.25 x 106 cells (data not shown). Because we were interested in determining whether rejection could be inhibited by CD4+ CD45RBlow cells, we have decided to use the minimum number of cells required to give a consistently high incidence of rejection. This number is 0.25 x 106. Therefore, in subsequent experiments 0.25 x 106 CD4+ CD45RBhigh cells will be used.



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  		FIGURE 2. CD4+ CD45RBlow cells prevent CD45RBhigh cells from causing rejection of a pancreas allograft. C57BL/6J-SCID mice were grafted with a pancreas harvested from a 1-day-old BALB/c donor. Three days later, groups of four recipients were injected i.v. with 0.25 x 106 CD4+ CD45RBhigh cells, n = 7 (a); 0.25 x 106 CD4+ CD45RBlow cells, n = 10 (b); no cells, n = 7 (c); or 0.25 x 106 CD4+ CD45RBhigh cells and 0.125 x 106 CD4+ CD45RBlow cells, n = 10 (d); 24 days after cell infusion, the mice were culled, and the grafts were fixed, sectioned, and stained for the presence of insulin (a–d). Original magnification, x100. Sections from each graft were analyzed for the presence of cellular infiltration (e) and islet area (f). The long arrow points to an islet and the short arrow points to a duct wall. (The p value for variance among all groups is <0.002 (ANOVA). Comparisons between two groups are as follows: p < 0.01 for high vs low (**); p < 0.05 for high vs high and low (*); and p < 0.05 for high vs no cells (*) (Bonferroni multiple comparison test).

 
CD4+ CD45RBlow cells prevent CD4+ CD45RBhigh cells from rejecting a pancreas allograft

Having established that CD4+ CD45RBlow cells were substantially less efficient at causing allograft rejection than CD45RBhigh cells, we determined whether the CD45RBlow population had the capacity to prevent the CD45RBhigh population from rejecting foreign tissue. The experiment was set up in the same way as above but with an additional group infused with both CD45RBhigh cells and CD45RBlow cells. A 1:1 ratio of high (0.25 x 106) to low (0.25 x 106), and a 2:1 ratio of high (0.25 x 106) to low (0.125 x 106) were used with similar results. Only the data for the 2:1 ratio are shown. Pancreas allografts in mice that had received a mixture of CD45RBhigh and CD45RBlow cells (Fig. 2God) were morphologically similar to those grafts in the groups that received CD45RBlow cells only (Fig. 2Gob) or no cells (Fig. 2Goc); that is, no signs of rejection were evident. Pancreas grafts from mice that had received CD45RBhigh and CD45RBlow cells displayed a significant increase in islet area compared with grafts from mice that had received CD45RBhigh cells only (p < 0.05). Therefore, these data suggest that CD4+ cells expressing low levels of CD45RB are able to prevent allograft rejection mediated by CD45RBhigh cells.

Pancreas allografts in recipients of a CD4+ CD45RBhigh and CD45RBlow cells are tolerant of graft Ags at 10 wk after grafting

The data shown thus far are taken at 3 wk after grafting. Therefore, it was important to determine whether allograft protection mediated by CD45RBlow cells was maintained for longer periods and whether the recipient was then rendered tolerant of graft Ags. Tolerance was tested using the classical method of placing a second graft into the recipient. Specifically, C57BL/6-SCID recipients were infused with a 1:1 ratio of CD45RBlow and CD45RBhigh cells, low-density cells only, or no cells. The first graft was placed 1 day before the cell infusion. The second graft, also a pancreas graft from a BALB/c donor, was placed under the contralateral kidney 6 wk later, and subsequently all grafts were removed for histologic examination after an additional 4 wk (see Fig. 3Go for time course of treatment).



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  		FIGURE 3. A diagrammatic view of the protocol used for experiments described in Fig. 4Go. The mice used in the experiments described in Fig. 4Go were grafted twice and given a cell infusion. This diagram shows the chronological order of the treatment given.

 
The first pancreas allografts from mice that received no cells showed no signs of rejection 10 wk after grafting (Fig. 4Goa). This was also true of the grafts taken from mice that received CD45RBlow cells only (Fig. 4Gob) or CD45RBlow and CD45RBhigh cells (Fig. 4Goc). Specifically, cellular infiltration was absent in all grafts from those three groups. In addition, islet area was not significantly different between groups and was comparable to the islet area seen in the single grafts described in Fig. 2Go. These data suggest that allograft survival was maintained long term.



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  		FIGURE 4. Pancreas allografts in recipients of a mixture of CD4+ CD45RBhigh and CD45RBlow cells are tolerant to the allograft. C57BL/6J-SCID mice were grafted with pancreas allografts from 1- to 3-day-old BALB/c donors. The following day they were divided into groups and injected with no cells, n = 3 (a); 0.25 x 106 CD45RBlow cells, n = 3 (b); or 0.25 x 106 CD45RBlow cells and 0.25 x 106 CD45RBhigh cells, n = 3 (c). Six weeks after placement of the first graft, all mice were grafted with a second 1- to 2-day-old BALB/c pancreas (d–f). Four weeks later the mice were culled and the grafts were prepared for histological examination. Original magnification, x100.

 
The islet area in the second grafts from mice that received no cells (Fig. 4God) or CD45RBlow cells only (Fig. 4Goe) were similar to grafts in mice in the groups that received both CD45RBlow and CD45RBhigh cells (Fig. 4Gof). Therefore, the protective effect of the CD45RBlow cells on the response of the CD45RBhigh cells seen in the long-term appears to be mediated by inducing functional tolerance at the whole animal level. Despite the fact that the islet area in the second grafts was maintained, cellular infiltration was observed in 100% of second grafts (Fig. 4Gof) but not first grafts (Fig. 4Goc) from the mice that had received the mixture of CD45RBhigh and CD45RBlow cells.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown that the CD4+ CD45RBhigh cell subset is sufficient for pancreas allograft rejection. In contrast, those CD4+ cells that express a low density of the CD45RB molecule do not reject a pancreas allograft and protect such allografts from rejection by CD4+ CD45RBhigh cells. This protection lasts for at least 10 wk and functional tolerance is shown in the protected recipients by the finding that second grafts in these recipients are also not rejected.

Our data confirm the finding that the CD4+ CD45RBlow cell subset is a regulatory cell subset capable of preventing pathological responses. It also extends these findings to show that the regulatory cells do not distinguish between self-Ag and foreign MHC Ag. This is in contrast to the published data which have suggested that the presence of self-Ag is critical to the development and function of the regulatory cells (16). The ability of CD45RBlow cells to regulate the response to foreign MHC Ags, therefore, might seem unexpected. However, this ability might reflect the high frequency with which T cells respond to foreign MHC Ags (33) and the consequent high frequency with which any T cell subset (including CD4+ CD45RBlow cells) might cross-react with foreign MHC Ags. Alternatively, a specific Ag might not be necessary for the CD45RBlow cells to function in a regulatory manner in this transplantation model. It is also possible that the CD45RBlow cells develop their regulatory function after contact with transplantation Ag in the grafted recipient.

There are a number of possibilities as to the mechanism by which the CD45RBlow cells prevent the CD45RBhigh cells from rejecting the allograft. They may prevent homing of the high cells to the graft. In this regard, we found that second grafts of recipients of CD45RBhigh and CD45RBlow cells display cellular infiltration within 4 wk of grafting, even though they contained an islet area equivalent to those of grafts from mice that received CD45RBlow cells only. This observation might indicate that the CD45RBlow cells are able to prevent naive cells, but not primed cells, from infiltrating the graft. Cellular infiltration was not observed in the first (established) grafts. Alternatively, the CD45RBlow cells might prevent priming of the high cells to the graft Ags, or they might affect the effector capacity of the graft-Ag-specific CD45RBhigh cells so that they are no longer pathogenic. Finally, the CD45RBlow cells might render the graft less immunogenic. Such effects might occur through cell-mediated events or through soluble mediators (16, 34, 35).

In summary, CD4+ CD45RBhigh cells are sufficient to induce pancreas allograft rejection. In contrast, CD4+ CD45RBlow cells prevent CD4+ CD45RBhigh cells from causing rejection. In the model described here the CD45RBlow cells are purified from a mouse that has not been previously immunized with the transplantation Ags in question. In addition, the ratio of CD45RBhigh to CD45RBlow cells used in the experiments described here was 2:1, which is the same as the ratio normally present in the spleen of untreated mice and the same as the ratio used to prevent autoimmune disorders (10, 11, 12, 13); this suggests that in this model the mechanism that prevents autoimmunity also prevents allograft rejection. In the context that fully immunocompetent mice do reject pancreas allografts whereas they do not normally show signs of autoimmunity, we have drawn the following series of possible conclusions: 1) in a fully immunocompetent animal, CD4+ CD45RBlow cells do not inhibit the ability of a greater number of CD4+ CD45RBhigh cells from rejecting an allograft; 2) CD4+ CD45RBlow cells do not inhibit the ability of other T and B cell subsets from causing rejection of an allograft; 3) in an immunocompetent mouse, a cell subset other than, or as well as, the CD4+ CD45RBlow cell subset prevents autoimmune disorders but not allograft rejection; or 4) the immunocompromised recipient model is unusually susceptible to the effect of CD4+ CD45RBlow cells. Further studies will indicate which, if any, of these possibilities is true.


   Footnotes
 
1 This work was supported by research Grant SFP 1249 from Novartis Pharma (to J.D.); by Grants DK55099 (to J.D.) and HD29764 and A139664 (to N.S.) from the National Institutes of Health; and a Diabetes Interdisciplinary Research Program grant from the Juvenile Diabetes Foundation (to N.S.). This is manuscript no. 12469-IMM from The Scripps Research Institute. Back

2 Address correspondence and reprint requests to Dr. Joanna D. Davies, Department of Immunology, IMM-23, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: Back

3 Abbreviations used in this paper: CD45RBhigh, CD45RB high density; CD45RBlow, CD45RB low density. Back

Received for publication July 8, 1999. Accepted for publication August 30, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kappler, J. W., N. Roehm, P. Marrack. 1987. T cell tolerance by clonal elimination in the thymus. Cell 49:273.[Medline]
  2. Kappler, J. W., U. Stearz, J. White, P. C. Marrack. 1988. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature 332:35.[Medline]
  3. MacDonald, H. R., R. Schneider, R. K. Lees. 1988. T-cell receptor Vß use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 332:40.[Medline]
  4. Rocha, B., H. von Boehmer. 1991. Peripheral selection of the T cell repertoire. Science 251:1225.[Abstract/Free Full Text]
  5. Ohashi, P. S., S. Oehen, K. Buerki, H. Pircher, C. T. Ohashi, B. Odermatt, B. Malissen, R. M. Zinkernagel, H. Hengartner. 1991. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65:305.[Medline]
  6. Oldstone, M. B., M. Nerenberg, P. Southern, J. Price, H. Lewicki. 1991. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65:319.[Medline]
  7. Coulombe, M., R. G. Gill. 1996. T lymphocyte indifference to extrathymic islet allografts. J. Immunol. 156:1998.[Abstract]
  8. Jenkins, M. K., C. A. Chen, G. Jung, D. L. Mueller, R. H. Shwartz. 1990. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J. Immunol. 144:16.[Abstract]
  9. Schwartz, R. H.. 1990. A cell culture model for T lymphocyte clonal anergy. Science 248:1349.[Abstract/Free Full Text]
  10. Fowell, D., A. J. McKnight, F. Powrie, R. Dyke, D. Mason. 1991. Subsets of CD4+ T cells and their roles in the induction and prevention of autoimmunity. Immunol. Rev. 123:37.[Medline]
  11. Powrie, F., M. W. Leach, S. Mauze, L. B. Caddle, R. L. Coffman. 1993. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C.B-17 scid mice. Int. Immunol. 5:1461.[Abstract/Free Full Text]
  12. Morrissey, P. J., K. Charrier, S. Braddy, D. Liggitt, J. D. Watson. 1993. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice: disease development is prevented by cotransfer of purified CD4+ T cells. J. Exp. Med. 178:237.[Abstract/Free Full Text]
  13. Powrie, F., R. Correa-Oliveira, S. Mauze, R. L. Coffman. 1994. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J. Exp. Med. 179:589.[Abstract/Free Full Text]
  14. Groux, H., A. O’Garra, M. Bigler, M. Rouleau, S. Antonenko, J. E. de Vries, M. G. Roncarolo. 1997. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737.[Medline]
  15. Fowell, D., D. Mason. 1993. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes: characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177:627.[Abstract/Free Full Text]
  16. Seddon, B., D. Mason. 1999. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor-ß and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+ CD45RC- cells and CD4+CD8- thymocytes. J. Exp. Med. 189:279.[Abstract/Free Full Text]
  17. Hao, L., Y. Wang, R. G. Gill, K. J. Lafferty. 1987. Role of the L3T4+ T cell in allograft rejection. J. Immunol. 139:4022.[Abstract]
  18. Shizuru, J. A., A. K. Gregory, C. T. B. Chao, C. G. Fathman. 1987. Islet allograft survival after a single course of treatment of recipient with antibody to L3T4. Science 237:278.[Abstract/Free Full Text]
  19. Gill, R. G., L. Wolf, D. Daniel, M. Coulombe. 1994. CD4+ T cells are both necessary and sufficient for islet xenograft rejection. Transplant. Proc. 26:1203.[Medline]
  20. Simeonovic, C. J., D. J. Brown, M. J. Townsend, J. D. Wilson. 1996. Differences in the contribution of CD4+ T cells to proislet and islet allograft rejection correlate with constitutive class II MHC alloantigen expression. Cell Transplant. 5:525.[Medline]
  21. Zhang, Z., R. Zhong, D. Grant, B. Garcia, M. White, C. Stiller, A. Lazarovits. 1995. Prevention and reversal of renal allograft rejection by monoclonal antibody to CD45RB in the mouse model. Transplant. Proc. 27:389.[Medline]
  22. Lazarovits, A. I., S. Poppema, Z. Zhang, M. Khandaker, C. E. Le Feuvre, S. K. Singhal, B. M. Garcia, N. Ogasa, A. M. Jevnikar, M. J. White, et al 1996. Prevention and reversal of renal allograft rejection by antibody against CD45RB. Nature 380:717.[Medline]
  23. Trowbridge, I., M. L. Thomas. 1994. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12:85.[Medline]
  24. Budd, R. C., J.-C. Cerrotini, C. Horvath, C. Bron, T. Pedrazzini, R. C. Howe, H. R. MacDonald. 1987. Distinction of virgin and memory T lymphocytes: stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J. Immunol. 138:3120.[Abstract]
  25. Birkeland, M. L., P. Johnson, I. S. Trowbridge, E. Pure. 1989. Changes in CD45 isoform expression accompany antigen-induced murine T-cell activation. Proc. Natl. Acad. Sci. USA 86:6734.[Abstract/Free Full Text]
  26. Bottomly, K., M. Luqman, L. Greenbaum, S. Carding, J. West, T. Pasqualini, D. B. Murphy. 1989. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur. J. Immunol. 19:617.[Medline]
  27. Lee, W. T., X.-M. Yin, E. S. Vitetta. 1990. Functional and ontogenic analysis of murine CD45Rhi and CD45Rlo CD4+ T cells. J. Immunol. 144:3288.[Abstract]
  28. Bradley, L. M., G. G. Atkins, S. L. Swain. 1992. Long-term CD4+ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J. Immunol. 148:324.[Abstract]
  29. Mueller, R., J. D. Davies, T. Krahl, N. Sarvetnick. 1997. IL-4 expression by grafts from transgenic mice fails to prevent allograft rejection. J. Immunol. 159:1599.[Abstract]
  30. Wallenstein, S., C. L. Zucker, J. L. Fleiss. 1980. Some statistical methods useful in circulation research. Circ. Res. 47:1.[Abstract/Free Full Text]
  31. Dialynas, D. P., Z. S. Quan, K. A. Wall, A. Pierres, J. Quintans, M. R. Loken, M. Pierres, F. W. Fitch. 1983. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J. Immunol. 131:2445.[Abstract]
  32. Birkeland, M. L., J. Metlay, V. M. Sanders, R. Fernandez-Botran, E. S. Vitetta, R. M. Steinman, E. Pure. 1988. Epitopes on CD45R (T200) molecules define differentiation antigens on murine B and T lymphocytes. J. Mol. Cell. Immunol. 4:71.[Medline]
  33. Fisher-Lindahl, K., D. B. Wilson. 1977. Histocompatibility antigen-activated cytotoxic T lymphocytes. II. Estimates of the frequency and specificity of precursors. J. Exp. Med. 145:508.[Abstract/Free Full Text]
  34. Powrie, F., M. W. Leach, S. Mauze, S. Menon, L. B. Caddle, R. L. Coffman. 1994. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1:553.[Medline]
  35. Powrie, F., J. Carlino, M. W. Leach, S. Mauze, R. L. Coffman. 1996. A critical role for transforming growth factor-ß but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183:2669.[Abstract/Free Full Text]



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Phil Trans R Soc B, September 29, 2005; 360(1461): 1713 - 1721.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B. V. Aruna, M. Sela, and E. Mozes
Suppression of myasthenogenic responses of a T cell line by a dual altered peptide ligand by induction of CD4+CD25+ regulatory cells
PNAS, July 19, 2005; 102(29): 10285 - 10290.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. M. Rushbrook, S. M. Ward, E. Unitt, S. L. Vowler, M. Lucas, P. Klenerman, and G. J. M. Alexander
Regulatory T Cells Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells during Persistent Hepatitis C Virus Infection
J. Virol., June 15, 2005; 79(12): 7852 - 7859.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. Gregori, P. Mangia, R. Bacchetta, E. Tresoldi, F. Kolbinger, C. Traversari, J. M. Carballido, J. E. de Vries, U. Korthauer, and M.-G. Roncarolo
An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells
J. Exp. Med., April 18, 2005; 201(8): 1293 - 1305.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
V. Smart, P. S. Foster, M. E. Rothenberg, T. J. V. Higgins, and S. P. Hogan
A Plant-Based Allergy Vaccine Suppresses Experimental Asthma Via an IFN-{gamma} and CD4+CD45RBlow T Cell-Dependent Mechanism
J. Immunol., August 15, 2003; 171(4): 2116 - 2126.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
R. D. Molano, A. Pileggi, T. Berney, R. Poggioli, E. Zahr, R. Oliver, C. Ricordi, D. M. Rothstein, G. P. Basadonna, and L. Inverardi
Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154
Diabetes, April 1, 2003; 52(4): 957 - 964.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
R. M. Sutherland, B. S. McKenzie, Y. Zhan, A. J. Corbett, A. Fox-Marsh, H. M. Georgiou, L. C. Harrison, and A. M. Lew
Anti-CD45RB antibody deters xenograft rejection by modulating T cell priming and homing
Int. Immunol., August 1, 2002; 14(8): 953 - 962.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Graca, S. Thompson, C.-Y. Lin, E. Adams, S. P. Cobbold, and H. Waldmann
Both CD4+CD25+ and CD4+CD25- Regulatory Cells Mediate Dominant Transplantation Tolerance
J. Immunol., June 1, 2002; 168(11): 5558 - 5565.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Sanchez-Fueyo, M. Weber, C. Domenig, T. B. Strom, and X. X. Zheng
Tracking the Immunoregulatory Mechanisms Active During Allograft Tolerance
J. Immunol., March 1, 2002; 168(5): 2274 - 2281.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. I. Kingsley, M. Karim, A. R. Bushell, and K. J. Wood
CD25+CD4+ Regulatory T Cells Prevent Graft Rejection: CTLA-4- and IL-10-Dependent Immunoregulation of Alloresponses
J. Immunol., February 1, 2002; 168(3): 1080 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
W. F. Ng, P. J. Duggan, F. Ponchel, G. Matarese, G. Lombardi, A. D. Edwards, J. D. Isaacs, and R. I. Lechler
Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells
Blood, November 1, 2001; 98(9): 2736 - 2744.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Hara, C. I. Kingsley, M. Niimi, S. Read, S. E. Turvey, A. R. Bushell, P. J. Morris, F. Powrie, and K. J. Wood
IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo
J. Immunol., March 15, 2001; 166(6): 3789 - 3796.
[Abstract] [Full Text] [PDF]

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