Senior Vice Chancellor's Research Seminar

Topic Overview:

Chalasani’s lab studies how B cells contribute to pathogenesis of alloimmunity and chronic rejection. Chronic rejection remains the primary cause of long-term failure of transplanted organs due to uncontrolled response of B and T cells to graft antigens. Among T cells, memory T cells play a significant role in perpetuating the alloimmune response that culminates in graft rejection. T cells also drive B cell differentiation and production of IgG antibodies that cause graft injury. Although antibodies are recognized as important mediators of chronic rejection, observations in mice and humans have shown that chronic rejection can occur in spite of undetectable alloantibodies, suggesting that antibody-independent pathways can also contribute to chronic rejection. Studies done by Chalasani and her lab members provide evidence that B cells play a key role in shaping T cell responses and causing chronic rejection via mechanisms other than antibody production.

Chalasani will describe studies in mice demonstrating that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies but requires the presence of B cells. Mice deficient in antibodies but not B cells experience chronic rejection the same as wild-type mice, whereas mice deficient in both B cells and antibodies are protected from chronic rejection. B cells contribute to chronic rejection by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice wherein B cells were present but could not present antigens, chronic rejection was markedly reduced. Also, graft-reactive effector and memory T cell responses were significantly diminished in chimeras lacking antigen presentation and CD40 costimulation by B cells but not antibodies. These findings establish that B cells contribute to pathogenesis of alloimmunity and chronic rejection by supporting T cell responses through antigen presentation, costimulation, and maintenance of lymphoid architecture.

Another series of studies tested if depleting B cells would be effective in curtailing T cell responses and limiting chronic rejection. Depleting B cells in naïve mice at transplantation enhanced graft-reactive T cell cytokine production and chronic rejection, suggesting that B cells could be immunomodulatory early in the alloimmune response. In contrast, depleting B cells later on after transplantation diminished graft-reactive T cell cytokine production and reduced chronic rejection, suggesting that B cells could be immunostimulatory after the initiation of the alloimmune response. Taken together, these results show that B cells play an important role in driving alloimmunity, and targeting B cells to inhibit chronic rejection requires careful consideration of timing and context.









		Topic Overview: Chalasani’s lab studies how B cells contribute to pathogenesis of alloimmunity and chronic rejection. Chronic rejection remains the primary cause of long-term failure of transplanted organs due to uncontrolled response of B and T cells to graft antigens. Among T cells, memory T cells play a significant role in perpetuating the alloimmune response that culminates in graft rejection. T cells also drive B cell differentiation and production of IgG antibodies that cause graft injury. Although antibodies are recognized as important mediators of chronic rejection, observations in mice and humans have shown that chronic rejection can occur in spite of undetectable alloantibodies, suggesting that antibody-independent pathways can also contribute to chronic rejection. Studies done by Chalasani and her lab members provide evidence that B cells play a key role in shaping T cell responses and causing chronic rejection via mechanisms other than antibody production. Chalasani will describe studies in mice demonstrating that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies but requires the presence of B cells. Mice deficient in antibodies but not B cells experience chronic rejection the same as wild-type mice, whereas mice deficient in both B cells and antibodies are protected from chronic rejection. B cells contribute to chronic rejection by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice wherein B cells were present but could not present antigens, chronic rejection was markedly reduced. Also, graft-reactive effector and memory T cell responses were significantly diminished in chimeras lacking antigen presentation and CD40 costimulation by B cells but not antibodies. These findings establish that B cells contribute to pathogenesis of alloimmunity and chronic rejection by supporting T cell responses through antigen presentation, costimulation, and maintenance of lymphoid architecture. Another series of studies tested if depleting B cells would be effective in curtailing T cell responses and limiting chronic rejection. Depleting B cells in naïve mice at transplantation enhanced graft-reactive T cell cytokine production and chronic rejection, suggesting that B cells could be immunomodulatory early in the alloimmune response. In contrast, depleting B cells later on after transplantation diminished graft-reactive T cell cytokine production and reduced chronic rejection, suggesting that B cells could be immunostimulatory after the initiation of the alloimmune response. Taken together, these results show that B cells play an important role in driving alloimmunity, and targeting B cells to inhibit chronic rejection requires careful consideration of timing and context.