b cells and allograft injury: more than you think geetha chalasani, md departments of medicine...
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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?
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
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
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 +
- -
+ -
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
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
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