The Banff 2022 Kidney Meeting Work Plan:Data-driven refinement of the Banff Classification for renal allografts

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell–mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.</p

The Banff 2022 Kidney Meeting Work Plan:Data-driven refinement of the Banff Classification for renal allografts

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell–mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.</p

Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells

Proliferative renewal of memory CD8 T cells is essential for maintaining long-term immunity. In this study, we examined the contributions that various tissue microenvironments make toward the homeostatic proliferation of Ag-specific memory CD8 T cells. We found that dividing memory T cells were present in both lymphoid and nonlymphoid tissues. However, the bone marrow was the preferred site for proliferation and contained a major pool of the most actively dividing memory CD8 T cells. Adoptive transfer studies indicated that memory cells migrated through the bone marrow and divided there preferentially. These results show that the bone marrow is not only the source of stem cells for generating naive T cells but also provides the necessary signals for the self-renewal of memory T cells

Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells

Proliferative renewal of memory CD8 T cells is essential for maintaining long-term immunity. In this study, we examined the contributions that various tissue microenvironments make toward the homeostatic proliferation of Ag-specific memory CD8 T cells. We found that dividing memory T cells were present in both lymphoid and nonlymphoid tissues. However, the bone marrow was the preferred site for proliferation and contained a major pool of the most actively dividing memory CD8 T cells. Adoptive transfer studies indicated that memory cells migrated through the bone marrow and divided there preferentially. These results show that the bone marrow is not only the source of stem cells for generating naive T cells but also provides the necessary signals for the self-renewal of memory T cells

IFN- dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses

CD8 T cells are necessary for costimulation blockade-resistant rejection. However, the mechanism by which CD8 T cells mediate rejection in the absence of major costimulatory signals is poorly understood. IFN-γ promotes CD8 T cell-mediated immune responses, but IFN-γ-deficient mice show early graft loss despite costimulation blockade. In contrast, we found that IFN-γ receptor knockout mice show dramatically prolonged graft survival under costimulation blockade. To investigate this paradox, we addressed the effects of IFN-γ on T cell alloresponses in vivo independent of the effects of IFN-γ on graft survival. We identified a donor-specific CD8 T cell breakthrough response temporally correlated with costimulation blockade-resistant rejection. Neither IFN-γ receptor knockout recipients nor IFN-γ-deficient recipients showed a CD8 breakthrough response. Graft death on IFN-γ-deficient recipients despite costimulation blockade could be explained by the lack of IFN-γ available to act on the graft. Indeed, the presence of IFN-γ was necessary for graft survival on IFN-γ receptor knockout recipients, as either IFN-γ neutralization or the lack of the IFN-γ receptor on the graft precipitated early graft loss. Thus, IFN-γ is required both for the recipient to mount a donor-specific CD8 T cell response under costimulation blockade as well as for the graft to survive after allotransplantation

Combination checkpoint blockade for metastatic cutaneous malignancies in kidney transplant recipients

Background Immune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection.Case presentations Here we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course.Conclusions These cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease

High-frequency alloreactive T cells augment effector function of low-frequency CD8+ T-cell responses under CD28/CD154 blockade

Background. Blockade of costimulatory molecules is a potent method of inducing long-term graft survival. We have previously addressed the issue of donor-reactive T-cell precursor frequency on relative costimulation dependence and found that the presence of a high precursor frequency of donor-reactive CD8+ T cells resulted in costimulation blockade-resistant graft rejection, whereas the presence of a low-frequency donor-reactive population did not. To address the mechanisms by which high-frequency T cells obviated the requirement for costimulation, we asked whether a low-frequency population responding concomitantly with a high-frequency response also demonstrated costimulation independence. Methods. A model system was established in which B6 mice containing a low frequency of anti-membrane bound chicken ovalbumin (mOVA) responders and a high frequency of anti-BALB/c responders received a skin graft from B6.mOVA×BALB/c F1 donors in the presence or absence of cytotoxic T-lymphocyte antigen-4 Ig/anti-CD154 costimulatory blockade. Results. The results revealed that in the presence of costimulation blockade, high-frequency anti-BALB/c T cells augmented the effector activity of low-frequency anti-mOVA T cells, but it did not enhance the accumulation of anti-mOVA T cells capable of mediating graft rejection. Conclusions. These results demonstrate that both antigen-specific and antigen-independent factors contribute to the relative costimulation independence of high-frequency T-cell responses