Interleukin-12 (IL-12) is a key immunoregulatory cytokine which promotes cell-mediated immunity. Its influence on the humoral immune response is less clearly defined. In this study, the effect of systemic IL-12 treatment on the T cell-dependent humoral immune response in the rat was examined using an experimental system in which PVG-RT1u congenic rats were immunized with class I Aa alloantigen in the form of a blood transfusion from the recombinant PVG.R8 rat strain. Administration of IL-12 following allo-immunization augmented the humoral immune response as determined by increased levels of cytotoxic anticlass I major histocompatibility complex antibodies. However, the effect of IL-12 on individual IgG isotypes was highly selective. Levels of allospecific antibodies of the IgG2b and IgG2c subclasses were markedly increased, whereas IgG1 alloantibody levels were profoundly reduced. The observed alterations in alloantibody response were dependent, in large part, on the stimulatory effect of IL-12 on interferon (IFN)-gamma production by T lymphocytes and natural killer cells, since they were abrogated by co-administration of neutralizing anti-IFN-gamma monoclonal antibody following alloantigen immunization.

Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass.

Cellular adhesion is mediated by distinct cell surface receptors (adhesion molecules) and plays a pivotal role in the biological processes of morphogenesis, cell migration and cell-cell communication. During the past decade many adhesion molecules have been identified and structurally analysed. This has allowed an understanding of their role in the pathophysiology of disease, including inflammation and sepsis, ischaemia and reperfusion, transplant rejection, atherosclerosis and thrombosis, angiogenesis and wound healing, as well as carcinogenesis and tumour metastasis. Understanding of the molecular mechanisms of cellular communication is not only vital for advances in surgical pathophysiology, it also has the potential to widen the spectrum of diagnosis and therapy of disease. Analysis of expression of individual surface molecules may help in the diagnosis of transplant rejection and allow a prognostic determination of tumour progression and metastasis formation. Moreover, manipulation of adhesion molecule function by monoclonal antibodies, antisense oligonucleotides or single gene products may open the door for novel therapeutic regimens to prevent transplant rejection and ischaemia-, sepsis- and shock-induced tissue injury.

Adhesion molecules as determinants of disease: from molecular biology to surgical research

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-6143.2003.00187.x

Serial peripheral blood perforin and granzyme B gene expression measurements for prediction of acute rejection in kidney graft recipients.

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Allorecognition pathways in transplant rejection and tolerance.

To study the role of perforin in cell-mediated graft rejection, vascularized hearts were grafted to perforin-deficient C57BL/6 and control C57BL/6 recipient mice. Fully allogeneic heart grafts (BALB/c) were acutely rejected by both recipients within 6 days. Peritoneal exudate lymphocytes from control mice but not from perforin-deficient mice exhibit a strong alloreactive cytotoxic activity in vitro. Histological analysis of the rejected tissues demonstrated extensive mononuclear cell infiltrates in both recipients. Flow cytometry analysis and immunohistology of graft-infiltrating cells showed similar proportions of lymphocyte subsets (CD8 >> CD4). Collectively, these data indicate that perforin is not essential in the cell-mediated acute rejection of a fully mismatched heart allograft. However, perforin-dependent effector mechanisms appeared to be limiting in the T cell-mediated rejection of heart allografts differing only at a single major histocompatibility complex class I antigen (bm1), because these grafts survived longer (mean 87.8 days) in perforin-deficient than in control mice (mean 31.5 days).

Acute rejection of vascular heart allografts by perforin‐deficient mice

Experimental studies of the T cell requirement for rejection of class I major histocompatibility complex (MHC)-disparate grafts have generated controversy over both the autonomy of CD8+ T cells and the mechanism whereby CD4+ T cells are able to independently mediate rejection. In this study of rejection of RT1Aa class I MHC-disparate rat cardiac and skin allografts by high-responder PVG RT1u recipients, we show that elimination of CD8+ T cells [by anti-CD8 monoclonal antibody (mAb) administration in vivo] fails to prolong graft survival, whereas partial depletion of CD4+ T cells (by anti-CD4 mAb treatment) markedly delays rejection of class I-disparate heart grafts, and marginally prolongs survival of skin grafts. Anti-CD4-treated PVG-RT1u athymic nude rats reconstituted with CD8+ T cells failed to reject class I-disparate skin grafts for several weeks and eventual rejection correlated with re-emergence of a small number of donor derived CD4+ T cells. Conversely, anti-CD8-treated nude rats reconstituted with CD4+ T cells alone rapidly rejected class I-disparate skin grafts. Passive transfer of anti-class I immune serum to anti-CD4-treated euthymic recipients promptly restored their ability to specifically reject a class I-disparate heart graft. Similarly, passive transfer of immune serum to PVG-RT1u nude rats bearing skin allografts caused destruction of class I-disparate but not third-party grafts. These results demonstrate that CD4+ T cells are both necessary and sufficient to cause rejection of class I-disparate heart and skin grafts in this model and that CD4+ T cell-dependent alloantibody plays a decisive role in effecting rejection.

CD4+ T cell-mediated rejection of major histocompatibility complex class I-disparate grafts: a role for alloantibody"

The ability of preoperative blood transfusion to extend the survival of organ allografts is well known but poorly understood. To study this phenomenon, adult PVG (RT1 c ) rats were rendered tolerant of DA (RT1 a ) cardiac allografts by prior donor-specific blood transfusion (DST). We investigated the cellular basis of the transfusion effect by adoptively transferring CD4 T cell subsets, obtained from thoracic duct lymph of tolerant rats, into cardiac allografted athymic PVG nude recipients. Surprisingly, CD4 T cells from DST rats evoked acute rejection on adoptive transfer. Evidence indicated that CD8 T cells played no role in DST-induced tolerance. Analysis of CD4 T cell subsets, defined in the rat by mAb OX22 (anti-CD45RC), revealed an unusual pattern of responsiveness. CD45RC + CD4 T cells (normally capable of inducing prompt rejection), when obtained from rats given a specific blood transfusion, were depleted of alloreactive cells and deficient at inducing rejection. In contrast, the cD45RC - subset (normally slow at evoking graft destruction) was highly active and ten-fold-enriched in its ability to induce rejection. Destruction of cardiac allografts by this latter subset was, however, completely inhibited by giving nude recipients a specific (but not a third-party) blood transfusion two weeks before heart grafting and cell transfer. Apparently, tolerance was maintained by residual elements of the prior blood transfusion that prevented the specific CD45RC - subset from regaining an alloaggressive capacity.

CD45RC+ CD4 T cell subsets are maintained in an unresponsive state by the persistence of transfusion-derived alloantigen.

During a primary response to thymus dependent antigens, B cells undergo a number of qualitative changes to become memory B cells - processes that require co-stimulatory signals and cytokine help from CD4 T cells. The question of whether distinct, antigen-experienced memory CD4 T cells are subsequently needed to program memory B cells into antibody synthesis has not been clearly resolved. Using an adoptive transfer model in which memory but not naive B cells were stimulated, we evaluated CD4 T cell help using lymphocytes obtained from primed or unprimed thymectomized donors and expressing a naive (CD45R(high)) or a memory (CD45R(low)) phenotype. Memory B cells, most of which were committed to the IgG1 (Th2) subclass, could be stimulated to produce antibody using help transferred by the CD45R(high) naive subset of unprimed donors (slow onset of response), the CD45R(low) subset of 7 day primed donors (large, rapid antibody response) or by both the CD45R(low) and the CD45R(high) "revertant" subsets of 6 month primed donors. We found that antigen primed CD45R(low) CD4 T cells reverted (defaulted) with time to a CD45R(high) resting state, a change that was prevented by persisting antigen. The evidence suggests that CD4 memory T cells are partitioned into two different functional states (CD45R(high) and CD45R(low)) and that these determine the characteristics of the memory B cell response in terms of speed, size and longevity.

Both CD45Rlow and CD45Rhigh "revertant" CD4 memory T cells provide help for memory B cells

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CD4+ T cell-mediated rejection of major histocompatibility complex class I-disparate grafts: a role for alloantibody"

CD45RC+ CD4 T cell subsets are maintained in an unresponsive state by the persistence of transfusion-derived alloantigen.

Both CD45Rlow and CD45Rhigh "revertant" CD4 memory T cells provide help for memory B cells