Download Memory T cells in Transplantation

B cells and allograft injury: more than you think
Geetha Chalasani, MD
Departments of Medicine (Renal-Electrolyte) and Immunology
Thomas E. Starzl Transplantation Institute
University of Pittsburgh School of Medicine
VA Pittsburgh Healthcare System
AKI Symposium – October 24, 2013
Long term allograft survival remains suboptimal
Chronic attrition
Chronic allograft rejection
• Alloantibodies
• Persistent effector and
memory T cells
Deceased donor grafts
Adapted from USRDS 2009 and OPTN/SRTR Annual Report 2009
Lamb et al, Am J Transplant 2011; 11: 450-462
Lodhi et al, Am J Transplant 2011; 11: 1226-1235
Antibodies
Cytokines
• 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
B cell
Costimulation
Antigen presentation
Formation of
tertiary lymphoid
tissues
What is the role of antibody-independent B cell functions in
alloimmunity?
Can B cells mediate chronic rejection independent
of antibodies?
BALB/c
(H2d)
MT
(has no B cells and antibodies)
or
s-/-xAID-/(has B cells but no antibodies)
or
wt
Wt and antibodies)
(has B cells
Heart
transplant
CTLA4Ig
and MR1
B6
>100 days
Chronic rejection?
Chronic rejection with intimal hyperplasia is not
dependent upon antibodies
B cells are sufficient and antibodies are not
necessary for chronic allograft vasculopathy
s-/-xAID-/B cells
into MT
B cells
Antibodies
+
+
+
-
-
+
-
B cells are sufficient for chronic rejection also in an
alternate model not requiring immunosuppression
Bm12
B cells
Antibodies
+
+
+
-
-
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
Cognate and non-cognate B cell functions
contribute to chronic rejection
Lymphoid
architecture
Cognate
B cells
Non-cognate
B cells
+
+
-
+
-
-
+
+
-
Cognate role of B cells are antigen presenting cells
in chronic rejection
MT + wt
or
MT + MHC (1 & 2) ko
MT B6
12
weeks
Heart allografts
Chimera
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
Splenic architecture in bone marrow chimeras
MT+wt
MT+MHCko
MT
CD4 MOMA B220
CR1/2 MOMA B220
B cells
B-APC
+
+
-
+
-
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
µMT+wt
µMT+MHCko
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 Ramaswami
Tripti Singh
Parmjeet Randhawa
Yue-Harn Ng
Qiang Zeng
Khalefathullah Sheriff
Frances Lund
University 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 monkeys
Kelishadi 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 Rejection
Clatworthy MR, Watson CJE, Plotnek G, Bardsley V, Chaudhry AN, Bradley
A, Smith KGC. University of Cambridge School of Clinical Medicine,
Cambridge CB2 2QQ, United Kingdom
N Engl J Med 2009; 360:2683-2685
Cytokine storm?
Breg depletion?
‘Naïve’ recipients?
Timing and context of B cell depletion should be considered carefully