Presentation is loading. Please wait.

Presentation is loading. Please wait.

Peripheral Control of Alloreactive B cells Anita Chong Section of Transplantation Department of Surgery.

Similar presentations


Presentation on theme: "Peripheral Control of Alloreactive B cells Anita Chong Section of Transplantation Department of Surgery."— Presentation transcript:

1 Peripheral Control of Alloreactive B cells Anita Chong Section of Transplantation Department of Surgery

2 Chong Lab YiJin LiDengping Yin LianLi Ma Jamie Kim JiKun Shen Anncy Varghese Jingwen Ding Tongmin Wang Audrea Troutman Nextran Gerry Byrne Hui Xu U Colorado Roberta Pelanda

3 Alloreactive B cells and Long-term Allograft Survival Alloantibodies mediate acute and chronic rejection Alloantibody-alloantigen complexes induce maturation of APC B cells can activate alloreactive T cells

4 Mechanisms of B cell tolerance Calame, Nat Immunol 2001:1103 Antigen CD40L

5 Nature Immunology 2, (2001) B cells and professional APCs recruit regulatory T cells via CCL4 Richard S. Bystry 1, Varuna Aluvihare 2, Katie A. Welch 1, Marinos Kallikourdis 1 & Alexander G. Betz 1 Using gene expression profiling, we show here that activation of B cells and professional antigen-presenting cells (APCs) induces the expression of common chemokines. Among these, CCL4 was the most potent chemoattractant of a CD4 + CD25 + T cell population, which is a characteristic phenotype of regulatory T cells. Depletion of either regulatory T cells or CCL4 resulted in a deregulated humoral response, which culminated in the production of autoantibodies. This suggested that the recruitment of regulatory T cells to B cells and APCs by CCL4 plays a central role in the normal initiation of T cell and humoral responses, and failure to do this leads to autoimmune activation.

6 Two-Phase model of T cell-dependent allo-specific B cell activation Modified from Baumgarth 2000 Immunol Rev. Secreted IgM

7 Extrinsic control of alloreactive B cells Inhibiting the development of effector T helper cells Inhibiting effective T-B cell interaction

8 Tolerance Model Day 0 C57BL/6 Day 60 + C57BL/6 Anti-CD40L (1 mg MR1/mouse; D-7, 0, 7) + DST (B/6) C57BL/6 (H-2 b ) into BALB/c (H-2 d ) mice

9 Anti-CD40L + DST induces allograft tolerance TreatmentGraft Survival None8 (x7), 9 + Anti-CD40L > 160 (x11) + 2nd heart >60 (x5), >100 (x3)

10 Tolerance can be dominantly transferred Tolerant mice reject third-party C3H hearts, exhibit linked tolerance to F1 (B/6 x C3H) hearts. A role of CD25 + T cells Allograft tolerance is associated with inhibited alloantibody production Features of Allograft Tolerance

11 Peripheral B cell Tolerance m Donor-specific (B/6) heart BCR-Ki B cells B/c recipients of B/6 heart Day Day 0: DST + MR1 Naïve

12 3.83 BCR-Ki B cells recognize K b antigens m H2-K(b) H2-K(d) Tetramer CD19

13 m Peripheral B cell Tolerance: 3.83 Cell Transfer + B/6 heart Days Post-B Cell Transfer O.D Anti-Id-IgM Naïve - No TxpTolRej

14 Peripheral B cell Tolerance: Lack of T cell help m Third-party C3H heart BCR-Ki B cells Day Day 0: DST + MR1 Naive

15 3.83 BCR-Ki B cells have dual alloreactivity m H2-K(b) H2-K(d) H2-K(k) Tetramer CD19

16 Peripheral B cell Tolerance: Lack of T cell help m Third-party C3H heart BCR-Ki B cells Day Day 0: DST + MR1 Naive

17 m Days Post-B cell Transfer Peripheral B cell Tolerance: Inhibition of T cell help

18 m B/6 heart BCR-Ki B cells + Anti-CD40 Day Day 0: DST + MR1 Naive

19 m Control of B cell Responses by limiting CD40-CD40L signals:

20 Peripheral B cell Tolerance: Regulation of T cell help m F1 (B/6 x C3H) heart BCR-Ki B cells Day Day 0 DST + MR1 Naive

21 m Linked Regulation of T cell Helper Responses Days Post-B Cell Transfer O.D Anti-Id IgM TolNaive

22 Cells Maintaining Peripheral B cell Tolerance m Spleen Cells from: i.Naïve ii.Tolerant (d60-120) iii.CD25-Depl Tolerant Scid recipients of B/6 heart

23 m Peripheral B cell Tolerance: Role of CD25 Cells

24 Peripheral suppression of alloantibody production: 1.Inhibiting the generation of T cell help 2.Dependent on CD25+ cells

25 m Regulation of T cell help C3H- T H cell Recpt. APC F1 antigens B/6xC3H 3.83 B cell B/6- T Tol/Reg C3H- T H cell No T cell Help T cell Zone B cell Zone B/6- T Tol/Reg Phase 1 Phase 2

26 Anti-carbohydrate Antibodies in Allograft transplantation Naturally occurring and elicited anti-A or anti-B antibodies Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation (Fan et al. 2004) Can peripheral mechanisms control anti-carbohydrate antibody responses?

27 Structure of Gal  1,3Gal and Blood Group A and B antigens CH 2 O H R OHOH O O O O O NHCOCH 3 OHOH OHOH OHOH OHOH OHOH CH 2 O H R OHOH O O O O O NHCOCH 3 OHOH OHOH OHOH OHOH O OHOH OHOH OHOH C3HC3H O CH 2 O H R OHOH O O O O O NHCOCH 3 OHOH OHOH OHOH O OHOH OHOH OHOH C3HC3H O Gal  1,3Gal-ß1,4GlcNAc Blood Group B Gal  1,3(Fuc  1,2)Gal Blood Group A GalNAc  1,3(Fuc  1,2)Gal

28 Tolerance Model Day 0 Gal + BALB/c Heart + Intact Active Bone Day 60 Gal + BALB/c Heart Anti-CD40L (1 mg MR1/mouse; D 0, 7, 14) C57BL/6-Gal -/- recipients tolerant to BALB/c-Gal +/+ grafts

29 IAB and anti-CD40L therapy induces allograft tolerance TreatmentMean None 7 d Anti-CD40L + IAB - 1st BALB/c heart> 130 d Anti-CD40L + IAB - 2nd BALB/c heart > 60 d

30 Features of IAB/Anti-CD40L-induced tolerance Tolerance can be dominantly transferred Tolerant mice reject third-party C3H hearts, exhibit linked tolerance to F1 (B/c x C3H) hearts. A role of CD25 + T cells Allograft tolerance is associated with suppressed alloantibody production

31 Anti-Gal IgM production in IAB/Anti-CD40L-induced tolerant mice O.D Days Post-Transplant Anti-Gal IgMb None MR1 + IAB

32 Peripheral B cell Tolerance m Donor-specific (B/c) heart Or Third-Party C3H heart + Anti-Gal BCR-Tg B cells B/6 GT -/- recipient of B/c heart Day Day 0: IAB + MR1 Naïve

33 IgMa + CD43 + CD21 + Madcam-1 IgMa

34 Anti-Gal IgMa production following challenge with BALB/c hearts Days Post-B cell Transfer Naive Tolerant

35 Anti-Gal IgMa production following challenge with C3H hearts Days Post-B cell Transfer Naive Tolerant

36 Conclusion Anti-Gal cell responses are inhibited even in the presence of effector T helper cells

37 m Regulation of B cell responses C3H- T H cell Recpt. APC Balb/c-Gal antigens T cell Help B/c- T Tol/Reg C3H-Gal antigens Recpt. APC Gal-B cell B/c- T Tol/Reg C3H- T H cell T cell Zone B cell Zone Phase 1 Phase 2

38 Extrinsic control of alloreactive B cells Inhibiting the generation of effector T helper cells Inhibiting the development of effector B cells

39

40 Histology of Spleen B/6 C3H F1 FDC-M1 B220

41 Peripheral B cell Tolerance: Effect of TI-B cell stimulation m Donor-specific (B/c) heart + Anti-Gal BCR-Tg B cells + CpG B/6 GT -/- recipient of B/c heart Day Day 0: IAB + MR1 Naïve

42 Inhibition of Anti-Gal IgMa production is reversed by CpG


Download ppt "Peripheral Control of Alloreactive B cells Anita Chong Section of Transplantation Department of Surgery."

Similar presentations


Ads by Google