B cells and allograft injury: more than you think

Geetha Chalasani, MD

Departments of Medicine (Renal-Electrolyte) and Immunology

Thomas E. Starzl Transplantation InstituteUniversity of Pittsburgh School of Medicine

VA Pittsburgh Healthcare System

AKI Symposium – October 24, 2013

Deceased donor grafts

Long term allograft survival remains suboptimal

Chronic attritionChronic allograft rejection• Alloantibodies• Persistent effector and memory T cells

Adapted from USRDS 2009 and OPTN/SRTR Annual Report 2009Lamb et al, Am J Transplant 2011; 11: 450-462

Lodhi et al, Am J Transplant 2011; 11: 1226-1235

Antibodies Cytokine

s

Antigen presentationFormation of

tertiary lymphoid tissues

B cell

• B cells express TLRs and respond to innate signals

• Proliferate and differentiate in an antigen specific manner

• B cells can modulate immune responses by various mechanisms

Chemokines

Costimulation

What is the role of antibody-independent B cell functions in alloimmunity?

Chronic rejection?

Wt>100 days

B6

BALB/c(H2d)

CTLA4Ig and MR1

MT (has no B cells and antibodies)

or ms-/-xAID-/-

(has B cells but no antibodies) orwt

(has B cells and antibodies)

Heart transplan

t

Can B cells mediate chronic rejection independent of antibodies?

Chronic rejection with intimal hyperplasia is not dependent upon antibodies

B cells are sufficient and antibodies are not necessary for chronic allograft vasculopathy

B cells + + - + Antibodies + - - -

ms-/-xAID-/- B cells

into mMT

B cells + + - Antibodies + - -

B cells are sufficient for chronic rejection also in an alternate model not requiring

immunosuppression

Bm12

Antibody and complement deposits in allografts

Alloreactive T cell responses are diminished in the absence of B cells

Graft vascular infiltration by T cells is diminished in the absence of B cells

Lymphoid + + -architecture Cognate + - - B cellsNon-cognate + + -B cells

Cognate and non-cognate B cell functions contribute to chronic rejection

Cognate role of B cells are antigen presenting cells in chronic rejection

MT B6

12 weeks

Chimera

MT + wt or

MT + MHC (1 & 2) ko Heart allografts

Chronic rejection?

Only B cells lack expression of MHC I and II in MT+MHCko chimeras so that antigen presentation specifically by B

cells and not by other APCs would be impaired

Expression of MHC on B cells and non-B cells in

bone marrow chimeras

mMT+wt mMT+MHCko

mMTCD4 MOMA B220

CR1/2 MOMA B220

B cells + B-APC +

- -

+ -

Splenic architecture in bone marrow chimeras

Chronic rejection is attenuated in the absence of antigen presentation by B cells

B cells + B-APC +

- -

+ -

Alloreactive T cell responses are diminished in the absence of antigen presentation by B

cells

Graft vascular infiltration by T cells is decreased in the absence of antigen

presentation by B cells

Summary

• B cells are sufficient and antibodies are not necessary for chronic rejection

• Antibody-independent functions of B cells drive

chronic rejection by supporting alloreactive T cell responses

B cells ≠ antibodies

B cells >> antibodies

Acknowledgements

Renee Ippolito Ke Jiang

Bala RamaswamiTripti Singh

Yue-Harn NgQiang Zeng

Khalefathullah Sheriff

Parmjeet Randhawa

Frances LundUniversity of Alabama

AHA Physician-Scientist Fellowship Award (Ng), AST-BMS Fellowship Award (Sheriff), Starzl Transplantation Fellowship Award (Jiang),

ASN Fellowship Award (Singh), Junior DOM Scholar Award, ROTRF and NIH-NIAID

Thank You!

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeysKelishadi SS, Azimzadeh AM, Zhang T, Stoddard T, Welty E, Avon C, Higuchi M, Laaris A, Cheng XF, McMahon C, Pierson RN 3rd. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.J Clin Invest. 2010 Apr 1;120(4):1275-84

• Less T cell infiltration• Decreased C4D• Decreased CAV despite antibodies in one recipient

It’s not all black and white ----

B-Cell–Depleting Induction Therapy and Acute Cellular RejectionClatworthy MR, Watson CJE, Plotnek G, Bardsley V, Chaudhry AN,

Bradley A, Smith KGC. University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, United KingdomN Engl J Med 2009; 360:2683-2685

Cytokine storm?Breg depletion?‘Naïve’ recipients?

Timing and context of B cell depletion should be considered carefully